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. HIV-associated lymphoma Burkitt lymphoma, DLBCL and 1 CNS lymphoma are most common, and m ostly seen in patients with very low CD4 counts. Incidence of NHL has d as a result of high ly active antiretroviral therapy (HAART). Hodgkin lym- phoma and indolent lymphoma less fre quent seen. Chemotherapy schedules used are identical to non-HIV patients. Administer HAART , prophylactic IT chemotherapy, and full-dose regimens with G-CSF as 1 prophylaxis. Post-transplantation LPD (PTLD) Occurs in <2% of organ transplant recipients. Risk highest in heart \200\223lung recipients. Monomorphic DLBCL most common; associated with immu- nosu ppressive therapy (esp. ATG) and EBV (main risk EBV mismatched transplant). Tends to involv e donor organ and multiple extranodal sites. Treatment ranges from reduction of immunosuppression (early lesions, hyperplasia and polymo rphic PTLD), single agent rituximab (achieves OR \211 75%, CR \211 69%) to more intense i mmunochemotherapy schedules (mono- morphic/HL subtypes) depending on subtype and morphology on biopsy. 201 AGGRESSIVE LYMPHOMAS Diff erent subtypes \200 Early lesions. \200 Plasmacytic hyperplasia. \200 Infectious mononucleosis \200\224like PTLD. \200 Polymorphic PTLD. \200 Monomorphic PTLD (B and T /NK cell types). \200 Classical HL-type PTLD. Immunohistochemical and cytogenetic features Diff use large B-cell lymphoma:1 pan-B markers (CD20+, CD79a+), gen- erally sIg+; Ki67 <90% favors DLBCL (cf. Burkitt >99%). 2 subgroups delineated by gene expression profi ling using DNA microarrays: germinal center-B-cell prof i le (GCB subtype: favorable; 760% 5-year OS) and acti- vated B-cell profi le (ABC subtype: unfavorable; 730% 5-year OS). Del(3) (q27) involving BCL-6 gene mutations 35%; t(14;18) 25 %; t(8;14) 15%. Mediastinal large B-cell lymphoma: pan-B markers (CD20+, CD79a+), often CD30+; sIg \210\222 ; gene expression profi le similar to classical HL. Mantle cell lymphoma: pan-B markers; CD5+, strong sIg, CD23 \210\222, cyclin-D1. t(11;14)(q 13;q32) involves IgH gene on chromosome 14, juxtaposes and dysregulates BCL-1 with overexpr ession of cyclin D1, a protein involved in cell cycle regulation, seen in 70%. Mature (peripheral) T-cell lymphomas: pan-T markers (CD3+, CD2+); TdT \210\222 (cf. precurs or T-lymphoblastic TdT+); Ki-67 has prognostic value. Angioimmunoblastic T-cell lymphoma: characteristic PAS+ arborizing venules in LN; pan-T mar kers, CD4+, TdT \210\222, CD10+, sometimes BCL-6+, CXCL13 overexpression; B-cells are EBV+. Anaplastic large cell lymphoma: pan-T markers but often CD3-; CD4+; TdT \210\222, CD30+, AL K+, or ALK \210\222. t(2;5)(p23;q35) in 60%. 1 cutaneous always ALK \210\222. Mycosis fungoides and S zary Syndrome Immunophenotyping: CD2+, CD3+, CD4+, CD5+, CD7 \210 \222, CD8 \210\222, CD25 \210\222 T cells. Cytogenetics: no typical pattern. Burkitt lymphoma Pan-B markers, CD10+, sIg+, Ki67 >99% (cf. DLBCL <90%), TdT \210\222. 80% t(8;14)(q24;q32), 15% t(2;8)(q11;q24), 5% t(8;22)(q24;q11) juxta- pose c-MYC with Ig gene l oci and cause MYC overexpression. Endemic cases have raised antibody titres to EBV antigens and multiple copies of EBV DNA in tumor (unusual in sporadic cases). Presence of t(14;18) associated with poor response to therapy. Precursor B-lymphoblastic: pan-B markers, sIg \210\222, CD10+, TdT+; variable cytogenetics. Precursor T-lymphoblastic: pan-T markers, TdT+; variable cytogenetics. 202 CHAPTER 5 Lymphoma Reference 1. Rosenwald, A. et al. (2002). The use of molecular profi ling to predict surviv al after chemotherapy for diff use large B-cell lymphoma. N Engl J Med, 346, 1937 \200\2234 7. Further reading Dreyling, M. et al. (2013). Update on the molecular pathogenesis and clinic al treatment of mantle cell lymphoma: report of the 11th annual conference of the European Mantle Cell Lymphoma Network. Leuk Lymphoma, 54(4), 699 \200\223707. Montoto, S. et al. (20 12). HIV status does not infl uence outcome in patients with classical Hodgkin lymphoma tre ated with chemotherapy using doxorubicin, bleomycin, vinblastine, and dacarbazine in the hi ghly active antiretroviral therapy era. J Clin Oncol, 30(33), 4111 \200\22316. 203 AGGRESSIVE LYMPHOMAS 204 CHAPTER 5 Lymphoma Initial treatment of aggressive lymphomas Clinical trial entry where possible. T-cell rich B-cell lymphoma and 1 mediastinal B-cell lymphoma treated as DLBCL. Localized DLBCL Stage I and non-bulky (mass <10cm) stage II disease without adverse prognos tic factors: \200 6 \227 R-CHOP (likely superior to CHOP, although stage I disease exclu ded from most trials) or R-CHOP \227 3 plus involved fi eld radiotherapy (IF-RT); PFS and OS >90%.2 Patients with bulky disease and/or local extranodal disease: treated with 6 courses of R-CHOP plus IF-RT (30 \200\22340 Gy).1 Patients with localized testicular DLBCL should have an orchidectomy, receive 6 courses of R-CHOP with IT CNS prophylaxis, followed by contralateral testicular RT. In the UK rituxima b in stage I disease is not NICE approved. Advanced stage DLBCL R-CHOP: Standard therapy if patient is able to tolerate. 6 cycles ever y 14d or 21d. Addition of rituximab has improved the CR rate (76% vs 63%), EFS (57% vs 38%) , and OS (70% vs 57%) at 2 years with no added toxicity.2 This was sustained on longer foll ow-up (5-year OS 58% vs 45%)3 and confi rmed in younger patients with DLBCL (3-year EFS 79% vs 59%).4 Easy administration and generally well tolerated. \200 Patients with testicula r, sinus, BM, or epidural involvement should receive concomitant CNS directed IT chemothera py prophylaxis (IT MTX \227 3 \200\2236). Some groups use a high IPI as requiring CNS prop hylaxis. All data on CNS relapse of DLBCL stems from the pre-rituximab era and views on CNS prophylaxis (agent, number of administrations, and in which patients) vary. Consider adjuvant RT to any site of bulk disease (>10cm) at diagnosis. Pros and cons of site of disease and age of patient need to be taken into consid eration. Data do not support maintenance rituximab. \200 Intensifi cation of initial therapy remai ns under investigation (R-EPOCH). Response assessment Evaluate response to initial therapy mid-treatment (unless response cli ni- cally apparent) by CT or PET/CT to identify non-response or progres- sion despite thera py. Complete 6 courses if \211 50% PR has been achieved. Repeat all +ve interim scans on c ompletion of therapy. If CR is not achieved further treatment should be considered. Follow-up Patients who achieve CR should be reviewed every 3 months for 24 months then ever y 6 months for 36 months.1 205 INITIAL TREATMENT OF AGGRESSIVE LYMPHOMAS Mantle cell lymphoma Incurable with conventional therapy. Not \201 t for intensive treatment: chlorambucil, CVP, FCR, or CHOP + rituximab may be ap propriate for patients not fi t for more intensive therapy. CHOP: OR rate 780% (CR 750%) wi th PFS <18 months and OS 3 years. Addition of rituximab improves responses. Fit for intensive treatment \200 NORDIC schedule: alternating R-maxi-CHOP \227 3 and HD cytarabine \227 3 followed by BEAM autograft (maxi-CHOP: cyclophosphamide 1200mg/m2, doxor ubicin 75mg/m2, vincristine 1.4mg/m2 (max. 2mg), prednisolone 100mg, HD cytarabine: 3000mg/ m2 4 doses per cycle (2000mg/m2 if >60 years). Standard treatment for fi t patients. Overal l and complete response 96% and 54% respectively. 6-year overall, event-free, and progressi on-free survival 70%, 56%, and 66%, respectively, with no relapses occurring after 5 years. R-HyperCVAD alternating with MTX and cytarabine: very intensive with high toxicity: 89%CR; 3-year FFS 80% in patients <65 years.5 R-EPOCH.6 Maintenance rituximab: improvement of RR and OS with addition of maintenance ritu ximab. Now generally recommended. Bortezomib: proteasome inhibitor; single agent (1.3mg/m2 SC d1, 4, 8, and 11 in 21d cycle \227 8 cycles) achieves 31% OR in relapsed or refrac- tor y MCL; median duration 9 months. Thalidomide and lenalidomide: show single-agent activity; in trials in com- bination with c hemotherapy and rituximab. May be suitable for older patients. SCT: high-dose treatment and autologous SCT recommended in 1st CR. Suitable patients with a sibling allogeneic SCT option should be consid- ered for an allograft. Relapsed patients w ith MCL who have not received a SCT and respond to salvage therapy should be considered for SCT. T/NK cell lymphoma and MF/S zary syndrome No consensus on optimal therapy.7 Both CHOP and gemcitabine-based regimens used. SCT should be considered in 1st CR. \200 ALK+ ALCL: CHOP \227 6. Very chemosensitive (5-year OS 60 \200\22390% following CHOP-type therapy). Consider additional IF-RT for stage I/ II disease. SCT reserv ed for relapse in eligible patients. ALK- ALCL: CHOP \227 6. Less chemosensitive (11 \200\22346% 5-year OS) and for stage III/I V consideration should be given to SCT consolidation in 1st CR or in salvage setting. PTCLU: inferior outcome to CHOP: 5-year OS <30%; SCT consolidation should be considered for stage III/IV in 1st CR. AITL: CHOP-type therapy can achieve 50 \200\22370% CR but 5-year OS only 10 \200\22330% due to early relapse or infective deaths. Consider SCT in 1st CR for st age III/IV. Nasal NK/T lymphomas: may respond to local RT plus chemotherapy and CNS prophylaxis. 206 CHAPTER 5 Lymphoma MF/S zary syndrome: there is no evidence that single-agent or combination chemotherapy improves survival. High response rates achieved but short duration s. Treatments used: phototherapy, bexarotene, vorinostat, liposomal doxorubicin, CHOP, gemc itabine. Allogeneic SCT should be considered in younger patients. Very aggressive lymphomas These lymphomas display an exponential growth rate, a tendency to involve BM and meninges. There is a high risk of tumor lysis and pre- treatment hydration plus rasburicase are essential. Non-endemic Burkitt lymphoma (BL) High remission rates (90% EFS) and long-term DFS achieved with inten- sive short duration (3 \200\2236 months) multiagent chemotherapy regimens incl uding high-dose MTX, high-dose cytarabine, etoposide, ifosfamide, and CNS-directed prophyla xis. Protocols designed for lymphoblastic lymphoma or ALL are inferior to specifi c BL prot ocols such as (R-) CODOX-M/IVAC. The role of high-dose therapy/SCT is uncertain but should be considered in relapsed setting. Patients who achieve CR should be reviewed every 3 month s for 24 months then every 6 months for 36 months. Lymphoblastic lymphoma Based on ALL treatment. Management in adults follows more successful intensive regimens in childhood (including CNS prophylaxis and mainte- nance). High CR rat es (785%) and 5-year DFS up to 45% reported. High relapse rates in adults; SCT (autologous/ allogeneic) should be consid- ered in early management in eligible adult patients. Consider allograft in eligible relapsed patients. Adult T-leukemia/lymphoma: see E p.178. References 1. NCCN Clinical Practice Guidelines in Oncology: Non-Hodgkin \200\231s Lymphoma s. M http:// www.nccn.org/professionals/physician_gls/f_guidelines.asp#site 2. Coiffi er, B. et al. (2002). CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diff use large-B-cell lymphoma. N Engl J Med, 346, 235 \200\223242 3. Feugier, P. et al. (2005). Long-term results of the R-CHOP study in the treatment of eld erly patients with diff use large B-cell lymphoma: a study of the Groupe d \200\231Etude de s Lymphomes de I \200\231Adulte. J Clin Oncol, 23, 4117 \200\22326. 4. Pfreundschuh, M. et al. (2006). CHOP-like chemotherapy plus rituximab versus CHOP-like c hemotherapy alone in young patients with good-prognosis diff use large B-cell lymphoma: a r andomized controlled trial by the Mabthera International Trial (MinT) Group. Lancet Oncol, 7, 379 \200\22391. 5. Lenz, G. et al. (2005). Immunochemotherapy with rituximab and cyclophosphamide, doxorubi cin, vincristine and prednisolone signifi cantly improves response and time to treatment fa ilure but not long term outcome in patients with previously untreated mantle cell lymphoma: results of a prospective randomized trial of the German Low Grade Lymphoma Study Group (GL SG) J Clin Oncol, 23, 1984 \200\22392. 6. Dreyling, M. et al. (2005). Early consolidation by myeloablative radiochemotherapy follo wed by autologous stem cell transplantation in fi rst remission signifi cantly prolongs pro gression- free survival in mantle cell lymphoma: results of a prospective randomized trial of the European MCL Network. Blood, 105, 2677 \200\22384. 7. Greer, J. (2006). Therapy of peripheral T/NK neoplasms. Hematology, 2006, 331 \200\2237. 207 INITIAL TREATMENT OF AGGRESSIVE LYMPHOMAS Further reading Fisher, R.I. et al. (2006). Multicenter phase II study of bortezomib in pat ients with relapsed or refractory mantle cell lymphoma. J Clin Oncol, 24, 4867 \200\22374. Ganti, A.K. et al. (2005). Hematopoietic stem cell transplantation in mantle cell lymphoma. Ann Oncol, 16, 618 \200\22324. Geisler, C. et al. (2008). Nordic Long-term progression-fre e survival of mantle cell lymphoma after intensive front-line immunochemotherapy with in vi vo \200\223purged stem cell rescue: a nonrandomized phase 2 multicenter study by the Nordic Lymphoma Group. Blood, 112(7), 2687 \200\22393. Griffi ths, R. et al. (2011). Addition of rituximab to chemotherapy alone as fi rst-line therapy improves overall survival in elderly patients with mantle cell lymphoma Blood, 118, 4808 \200\22316. Kenkre, V.P. et al. (2011) . Maintenance rituximab following induction chemo-immunotherapy for mantle cell lymphoma: l ong-term follow-up of a pilot study from the Wisconsin Oncology Network. Leuk Lymphoma, 52( 9), 1675 \200\22380. Raty, R. et al. (2012). Prolonged immunochemotherapy with rituximab, c ytarabine and fl udarabine added to cyclophosphamide, doxorubicin, vincristine and predniso lone and followed by rituximab maintenance in untreated elderly patients with mantle cell l ymphoma: a prospective study by the Finnish Lymphoma Group. Lymphoma, 53(10), 1920 \200\223 8. Romaguera, J.E. et al. (2005). High rate of durable remissions after treatment of newly diagnosed aggressive mantle-cell lymphoma with rituximab plus hyper-CVAD alternating with r ituximab plus high-dose methotrexate and cytarabine. J Clin Oncol, 23, 7013 \200\22323. Sch ulz, H. et al. (2007). Immunochemotherapy with rituximab and overall survival in patients w ith indolent or mantle cell lymphoma: a systematic review and meta-analysis. J Natl Cancer Inst, 99, 706 \200\22314. 208 CHAPTER 5 Lymphoma Salvage therapy in aggressive lymphomas Patients who relapse or fail to achieve remission w ith initial therapy have a poor prognosis. Without eff ective 2nd-line (salvage) therapy, a lmost all die of progressive lymphoma in a median period of 3 \200\2234 months. A signifi c ant proportion of patients with DLBCL who relapse from 1st CR can be salvaged but prognosis for 1 refractory NHL is very poor. Conventional salvage chemotherapy Several salvage schedules are available with similar resp onse rates and none is clearly superior. There is therefore no \200\230standard \200\231 t reatment and there will be geographical and institutional diff erences. Generally ritux- im ab is added to salvage regimens although the evidence base in mainly the refractory setting for this is lacking. Schedules used: R-DHAP, R-EPOCH, R-ESHAP, R-ICE, R-mini-BEAM. Eligible patients (age <65 years) who respond to 2nd-line therapy (PR or CR) should receive high-dose therapy (e.g. BEAM or LEAM) followed by autologous SCT. 750% of those achieving CR are long-term disease-free and may be cured.1 High-dose therapy (HDT) and SCT HDT followed by peripheral blood stem cell harvest (PBSCH) and autol- ogous SCT is used to treat patients with relapsed or refractory aggres- sive or very aggressive NHL. In DLBCL the overall survival of 53%. This is clearly superior to conv entional dosage salvage therapy (5-year EFS 12%; OS 32%).2 Best results are obtained when l ymphoma still respon- sive to conventional dosage therapy and SCT performed in a state of m inimal residual disease. HDT is generally preceded by 2 \200\2233 cycles of salvage chemoth erapy. Syngeneic and allogeneic transplants have been used less frequently but are associated with cures. Patients who relapse after autologous SCT can sometimes be salvaged with an allogen eic SCT. New agents Bortezomib, lenalidomide, mTOR inhibitors, other monoclonal anti- bodies, and ta rgeted treatment are in ongoing clinical trials in either combination or as single agents. References 1. Cheson, B.D. et al. (2007). Revised response criteria for malignant lymphoma. J Clin Oncol, 25, 579 \200\22386. 2. Philip, T. et al. (1995) Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses. of chemotherapy -sensitive non-Hodgkin \200\231s lymphoma. N Eng l J Med, 333, 1540 \200\2235. 209 RESPONSE CRITERIA FOR LYMPHOMA Response criteria for lymphoma See Table 5.8 for the response criteria. Table 5.8 Response criteria for lymphoma (including PET)1 Response De \201 nition Nodal masses Spleen, liver BM Infi ltrate cleared on repeat biopsy; if indeterminate by morphology, immunohisto- chemitry should be \210\222ve Not palpable, nodules disappeared (a) FDG-avid or PET +ve prior to therapy: mass of any size permitted if PET \210\222ve; (b ) Variably FDG-avid or PET \210\222ve: regression to n size on CT Disappearance of all evidence of disease Complete response (CR) Irrelevant if +ve prior to therapy; cell type should be specifi ed. 50% decrease in SPD of nodules (for single nodule in greatest transverse diameter); no incr ease in size of liver or spleen 50% decrease in SPD of up to 6 largest dominant masses; no increase in size of other nodes (a) FDG-avid or PET +ve prior to therapy: \211 1 +ve at previously involved site (b) Varia bly FDG-avid or PET \210\222ve: regression on CT Regression of measurable disease and no new sites Partial response (PR) (a) FDG-avid or PET +ve prior to therapy; PET +ve at prior sites of disease and no new site s on CT or PET (b) Variably FDG-avid or PET \210\222ve; no change in size of previous lesi ons on CT Failure to achieve CR/ PR or PD Stable disease (SD) New or recurrent involvement >50% increase from nadir in the SPD of any previous lesions Appearance of a new lesion(s) >1.5cm in any axis, 50% increase in SPD of >1 node, or 50% in crease in longest diameter of a previously identifi ed node >1cm in short axis. Lesions PET +ve if FDG-avid lymphoma or PET +ve prior to therapy Any new lesion or increase 50% of previously involved sites from nadir Relapsed disease or progressive disease (PD) Reference 1. Cheson, B.D. et al. (2007). Revised response criteria for malignant lymphoma. J Clin Oncol, 25, 579 \200\22386. 210 CHAPTER 5 Lymphoma Role of FDG-PET scanning in NHL diagnosis and treatment1 CT is a reliable technique for pre -treatment staging but is inadequate for assessment of patients with apparent incomplete re solution of, usually previously bulky, nodal sites after therapy. Pre-treatment PET/CT is n ot currently standard but does facilitate interpretation of equivocal post- therapy scans e specially DLBCL. At restaging a +ve PET scan is predictive of relapse in DLBCL (785%) and t he \210\222ve predictive value is strong (85%). PET is more accurate than CT for response assessment. Diff erent NHL subtypes have diff ere nt/variable FDG uptake. DLBCL, BL & MCL are generally FDG-avid; indolent lymphomas are gene rally much less avid. T-NHL has variable FDG-avidity. PET/CT might have a role in diag- nos ing/excluding high-grade transformation seen in low-grade NHL. False +ve avidity occurs due to infl ammation, infection, granulomatous disease, brown fat, thymic hyperplasia, marrow and splenic hyperplasia after G-CSF, previous radiotherapy. A g ap of at least 3 weeks after chemotherapy and 8 \200\22312 weeks after radiotherapy is reco mmended. False \210\222ve fi ndings occur due to lesions below scanner resolution (5 \200\22310mm), too brief an interval between injection and scan (2h recom- mended), masking of tumor by p hysiological uptake by brain, heart, renal or GI tract, and in case of hyperglycaemia reduc ing uptake by tumor. Reference 1. Seam, P. et al. (2007). The role of FDG-PET scans in patients with lymphoma. B lood, 110, 3507 \200\22316. 211 ROLE OF FDG-PET SCANNING IN NHL DIAGNOSIS AND TREATMENT 212 CHAPTER 5 Lymphoma CNS lymphoma 1 CNS lymphoma (PCNSL)1 \200\2233 2 \200\2233% of NHL cases; 3% of all brain tumors. \200 Incidence i 3 \227 1990s and early 2000 partly due to the HIV pandemic (oc curs mainly when CD4s < 50/ L; Incidence is now falling due to early intervention and succ ess of HAART. Non-HIV related PCNSL occurs in ages 55 \200\22370 years; Usually classifi ed as a DLBCL, occasionally BL-like. Commonly involving the frontal lobes, corpus callosum, or deep periventricular structures; may involve eyes, meninges, or spinal cord; Simultanous systemi c lymphoma uncommon. Commonly presents with focal neurological defi cit, cognitive or personality change, sympto ms of raised intracranial pressure (headache and vomiting); 10% seizures; cauda equina synd rome; spinal cord disease causes neck or back pain or myelopathy. LP (if safe, exclude raised ICP fi rst) for CSF cytology gives variable results: fl ow cytometry and PCR analysis for Ig gene re-arrangement may help. Imaging: MRI or CT. No role for PET/CT. \200 Diagnosis by stereotactic needle biopsy. Not e: diagnostic accuracy is improved by avoiding routine use of steroids for cerebral oedema; steroids should therefore only be used in emergency. 50% relapse risk; most relapses in CNS, others mainly leptomeningeal and ocular, <10% systemic. Treatment Systemic treatment has largely superseded IT treatment due to adequate penetratio n of blood \200\223brain barrier with high doses of chemotherapy. Unfi t for systemic chemotherapy: steroids and whole-brain radiotherapy (WBRT); palliative approach. Fit for systemic chemotherapy: \200 Optimal schedule remains unclear but in patients fi t for intensive chemotherapy, the schedule should include methotrexate in adequate dose (>3g/m2) with folin ic acid rescue. Addition of HD Cytarabine (2000 mg/m2 for 4 doses) is recommended. Improves RR but no documented OS as yet. <60yr addition of WBRT is recommended \200 >60yrs no WBRT or attenuated dose WBRT recomme nded. Delayed neurotoxicity post-WBRT is common especially in older patients (5-year cumulative incidence 24%): progressive subcortical dementia, psychomotor slowing, memory dysfunction, behaviora l changes, ataxia, urinary dysfunction, and incontinence. Consolidation of response to high-dose MTX-based therapy (without WBRT) with thiotepa-based high-dose treatment and auto-SCT has produced prolonged responses in patients with poor pr ognostic features and can be considered. Patients who relapse after chemotherapy/SCT may respond again to WBRT if not previously administered. 213 CNS LYMPHOMA Ocular lymphoma \200 Intraocular lymphoma presents as ocular fl oaters and blurred vision ; It can progress to involve both eyes; 50% develop brain involvement; 15% of PCNSL develop concurrent or later eye involvement; \200 Standard therapy is fractionated radiotherapy (35 \200\22340 Gy over 5 weeks) to globe and contralateral globe with consideration of syst emic chemotherapy (including high-dose MTX) to prevent CNS relapse. See E Primary CNS lymph oma (PCNSL), E p.211. 2 CNS lymphoma \200 Systemic NHL with CNS involvement or CNS relapse post-treatment for systemic NHL. Usually meningeal involvement; occurs in up to 10% of cases of NHL. \200 Poor prognosis; median survival <3 months. \200 In fi t patients a treatment schedule similar to that use d in PCNSL can be considered. References 1. DeAngelis, L.M. and Iwamoto, F.M. (2006). An update on therapy for primary ce ntral nervous system lymphoma. Hematology Am Soc Hematol Educ Program, 2006, 311 \200\22316 . 2. Hochberg, F.H. et al. (2007). Primary CNS lymphoma. Nat Clin Pract Neurol, 3, 24 \200 \22335. 3. NCCN Clinical Practice Guidelines in Oncology: Central Nervous System Cancers. M http://www.nccn.org/professionals/physician_gls/f_guidelines.asp#site Further reading Ferreri, A.J.M. et al. (2009). High-dose cytarabine plus high-dose methotre xate versus high- dose methotrexate alone in patients with primary CNS lymphoma: a randomiz ed phase 2 trial. Lancet, 374, 1512 \200\22320. 214 CHAPTER 5 Lymphoma Hodgkin lymphoma (HL) First described by Thomas Hodgkin in 1832. Clinical presentation vari es but often asymptomatic. Treatment decisions are preferably made in a multidisciplinary s etting. Incidence \200 1% cancer registrations per annum. Annual incidence 73 per 100,000 in Europe and USA (less common in China and Japan). Bimodal age incidence \200\224major peak between 20 and 29 years and 2nd smaller peak at 60 years; median age 35; >90% of cases age 16 \200\22365. \200 Overall higher incidence in \231\202. Nodular sclerosing (NS) histology is most common subtype in young adults (>75% o f NS cases are <40 years) and has a \231\200 preponderance. Risk factors \200 Familial: 99 \227 i risk in identical twins; 7 \227 risk for siblings of young adults (no i for sibs of older adults); ?genetic or environmental eff ect. EBV: 4 \227 i risk of HL in individuals with history of infectious mononucleosis with median interval of 4.1 years;1 EBV encoded nuclear RNAs detected in Reed \200\223Sternberg (RS) cells; 26 \200\22350% cases +ve for EBV by molecular analysis (esp. mixed cellularity (MC) HL). HIV: 78 \227 i risk of HL; usually when good CD4 counts (usually patients with known diagn osis and on HAART); usually EBV+; associated with advanced stage at presentation, unusual s ites, and subsequent poorer outcome. Pathophysiology Cell of origin historically controversial. Single-cell PCR for Ig gene ampl i- fi cation demonstrated that the neoplastic cells in HL are clonal germinal center (GC) o r post-GC B-lymphocytes. HL therefore considered B-cell lymphomas. \200 RS cells: seen in classical HL: appear to be transformed post-germinal center B-cells with re-arranged but non-expressed Ig genes (due to crippling mutations) des tined for apoptosis that survive through several mechanisms including latent EBV infection, NF- B expression and a permissive infl ammatory cell infi ltrate. Lymphocytic and histiocytic (L&H) \200\230popcorn \200\231 cells in nodular lymphocyte-predominant HL are neoplastic germinal center B cells that express BCL-6; freque ntly have translocations involving bcl-6; usually EBV \210\222ve. Histology and classi \201 cation The WHO classifi cation puts HL into 2 distinct entities (E Table 5.1, pp.183 and 184): classical HL and nodular lymphocyte-predominant HL. Both hav e a diff erent immunophenotype, natural history, and response to therapy. Classical HL Most common; large mononuclear (Hodgkin cells) or binucleate/multi- nuclear RS cells make up only 1 \200\2232% of the cellularity of the lymph node. 215 HODGKIN LYMPHOMA (HL) These cells are CD30+ and typically CD3 \210\222, CD15+, CD20 \210\222, CD45 \210\222, CD75 \210\222, CD79a \210\222. 4 histological subtypes are identifi ed. Diff erential diagnosis: anaplastic large cell lymphoma; peripheral T-cell NHL; DLBCL; T-ce ll rich B-cell lymphoma; mediastinal large B-cell lymphoma. \200 Nodular sclerosing HL (N SHL): 780%; prominent bands of fi brosis and nodular growth pattern; lacunar Hodgkin cells; variable numbers of RS cells. Mixed cellularity HL (MCHL): 717%; mixed infi ltrate of lymphocytes, eosinophils, and histiocytes with classical RS cells. Lymphocyte depleted HL (LDHL): rare; diff use hypocellular infi ltrate with necrosis, fi brosis, and sheets of RS cells. Lymphocyte rich classical HL (LRCHL): uncommon; diff use predominantly lymphoid infi ltrate with scanty RS cells of \200\230classical \200\231 phen otype. Nodular lymphocyte-predominant HL (NLPHL) 3 \200\2238%; contains large atypical B cells L&H \200\230popcorn \200\231 cells. These are CD30 \210\222, CD15 \210\222, CD3 \210\222, CD2 0+, CD45+, CD75+, CD79a+ and BCL-6 protein+, EMA \210\222. Typical RS cells absent. L&H cel ls associated with CD4+/CD57+ T-cell rosettes. Nodules contain CD21+/CD35+ follicular dendr itic cell meshwork. No evidence of EBV. Diff erential diag- nosis: T-cell rich B-cell lymph oma; lymphocyte-rich classical HL. Clinical features Often presents with asymptomatic lymphadenopathy (often cervical); Initia l mode of spread occurs predictably to contiguous nodal chains. Waldeyer \200\231s ring inv olvement is rare and suggests a diagnosis of NHL. Lymphadenopathy in HL may wax and wane du ring observation. \200 Spleen involved in 730%; hepatomegaly 5%. Abdominal lymphadenopathy is unusual without splenic involvement. Bulky mediastinal and hilar lymphadenopathy may produce local symptoms (e.g. bronchial or SVC compression) or direct extension (e.g. to lung, pericardium , pleura, or rib). Pleural eff usions in 20%. Extranodal spread and BM involvement rare. Presence of disseminated extranodal disease is generally accompanied by generalized lymphadenopathy and splenic involvement and usually a late event. 33% patients have \211 1 associated \200\230B \200\231 symptom at presentation; \200\230 B \200\231 symptoms correlate with disease extent, bulk, and prognosis. Sometimes: generalized pruritus and alcohol-induced lymph node pain. \200 A defect in cel lular immunity has been documented in patients with HL: i risk of infections (TB, fungal, p rotozoal, and viral infections). NSHL: typically in young adults (median age 26 years); usually localized involving cervical , supraclavicular and mediastinal nodes; good prognosis if stage I/II. MCHL: median age 30 years but more prevalent in pediatric and older patients; associated wi th advanced stage and intermediate prognosis. LDHL: more common in older adults; often extensive disease relatively poor prognosis. Most frequently seen in HIV patients. 216 CHAPTER 5 Lymphoma LRCHL: \231\202> \231\200; tendency to localized disease; favorable prognosis. NLPHL: more frequent in \231\202 (2 \200\2233 \227); median age 35 years; typically localized at pre sentation; usually cervical or inguinal; infrequent \200\230B \200\231 symptoms; indolent course; late relapses occur; favorable prognosis; 10-year OS 80 \200\22390%. Investigation, diagnosis, and staging \200 Clinical history: B symptoms, alcohol intolera nce, pruritus, fatigue, and performance status. Lymph node excision biopsy; FNA inadequate. Multiple biopsies of suspicious nodes may be ne cessary as hyperplastic nodes may occur. FBC: may show normochromic normocytic anemia, reactive leucocytosis, eosinophilia, and/or a reactive mild thrombocytosis. ESR. \200 U&E and LFTs. \200 Urate and LDH. \200 HIV serology recommended in all pati ents. \200 CXR. \200 PET/CT whole body or CT neck, chest, abdomen, and pelvis. \200 B M trephine biopsy: in patients with stage IB/IIB or III/IV disease (not essential in stage IA/IIA disease). Fertility counseling; egg harvesting or semen cryopreservation prior to chemotherapy or pelvic radiotherapy if appropriate. Cardiac ejection fraction and pulmonary function tests if ABVD or BEACOPP planned. Ann Arbor staging Accurate staging is critical to selection of the most appropriate therapy . The Ann Arbor staging classifi cation has strong prognostic value and is determined by th e number of lymph node regions (not sites) involved and the presence or absence of \200 \230B \200\231 symptoms (E Table 5.9). The Cotswolds modifi cation refl ects the use of mod ern imaging techniques and recognizes and clarifi es diff erences in disease distribution a nd bulk. 217 HODGKIN LYMPHOMA (HL)