0 or 1 2 3 4 or 5 Low Low/intermediate Intermediate/high High 87% 67% 55% 44% 70% 50% 49% 40% 73% 51% 43% 26% A predictive model for aggressive non-Hodgkin s lymphoma. The International Non- Hodgkin s Lymphoma Prognostic Factors Project. (1993) N Engl J Med, 329, 987 \200\223994. Treatment of indolent lymphomas FL and SLL comprise the majority of patients and are treate d in a similar way. These diseases are usually responsive to chemotherapy and radio- 05-lymphoma.qxd 10.12.2003 04.13 PM Page 201 Lymphoma therapy but unless truly localized, inevitably recur. There is no firm evi- dence of a cura tive therapy for advanced disease. Many patients have few or no symptoms; the decision to i nitiate treatment and choice of treat- ment must take account of individual quality of life issues. At each stage, the pros and cons of treatment options should be shared with the pa tient to reach an agreed treatment decision. 201 Initial treatment of localized FL and SLL Involved field radiotherapy (35 \200\22340Gy) may be curative in the few patients with localized disease. 5-year DFS >50% may be expected. R ecurrence generally outside radiation field. Late relapses occur. Addition of chemotherapy improves DFS but not overall survival. Initial treatment of advanced FL and SLL Three options are available: (1) watch and wait; ( 2) conventional chemotherapy and/or radiotherapy; (3) intensive chemotherapy and/or radioth erapy. Watch-and-wait: therapy may be deferred for many months/years after diagnosis until clinica l symptoms develop. Patients may have better quality of life and avoid exposure to cytotoxi c agents but must be monitored closely to prevent or identify insidious complications promp tly. Overall survival >80% at 5 years. Conventional therapy: generally involves one of the following approaches: 2 Chlorambucil (0 .1 \200\2230.2mg/kg/d x 7 \200\22314 days, q28 or 0.4 \200\2230.6mg/kg every 2 weeks) or cy clophosphamide (50 \200\223150mg/d PO) as single agents or with prednisolone; response rate s of 50 \200\22380% after 12 \200\22318 months \200\231 treatment; most relapse within 5 ye ars; convenient oral regimen; well tolerated. 2 \200\230Simple \200\231 combination chemotherapy e.g. CVP: more rapid response than chlorambucil (useful with bulky disease or symptomatic patients) but otherwise similar : response rates 80 \200\22390%; median response 1.5 \200\2233 years; few durable remission s; IV and oral regimen; causes alopecia. 2 \200\230High grade \200\231 regimens: high \200\230CR \200\231 rates ( 60%) with CHOP-type regi- mens but continuous pattern of relaps e and overall survival not con- vincingly improved in indolent FL (histological grades I an d II). In histological \200\230grade III \200\231 FL CHOP produces results equivalent to t hose in DLBCL (see below). 2 Radiotherapy for treatment of local problems e.g. cord compression. Intensive therapy: patients with high tumor burden and high LDH who achieve CR have signifi cantly longer survival (63% at 10 years). To improve the CR rate high dose chemotherapy TBI followed by autologous SCT (with monoclonal antibody purging of the \200\230graft \200 \231 in some centers) has been utilized in younger patients with advanced FL and/or poor pr ognostic features after initial response to chlorambucil or CHOP. 80% CR rate; 66% overall survival and up to 40% DFS at 8 years. Still largely investigational; continuing risk of r elapse; too early to assess effect 05-lymphoma.qxd 10.12.2003 04.13 PM Page 202 on long term survival. Myelodysplasia develops in up to 15% of heavily pre-treated long-ter m survivors. Relatively few allografts have been undertaken. Most use TBI-containing conditioning. CR ra te >80% and relapse rates are clearly lower than after autograft (12% vs. 55% at 5 years) a nd very few after 2 years. Curative potential requires longer follow-up. The benefit of bet ter disease control is offset by a higher treatment-related mortality (15 \200\22330%). Non -myeloab- lative regimens may reduce toxicity, preserve the GvL effect and widen the availa bility of this treatment. AlloSCT should be considered in appro- priate patients with poor prognosis disease. Total lymphoid (or nodal) irradiation may achieve very high CR rates wit h 5-year DFS rates >60% but is rarely utilized due to toxicity. 202 Further treatment of indolent lymphomas When indolent lymphoma progresses after a partial o r complete response to initial therapy, it is important to rule out transformation to DLBCL (esp. if LDH 4, LN rapidly enlarging, constitutional symptoms, extranodal disease). In rec urrent indolent NHL, further responses can be achieved with the prior therapy in most patie nts who have achieved a durable response (>12 months). However, chemoresistance to alkylati ng agents ultimately develops. Interferon-a maintenance: several large randomized trials demonstrate a beneficial effect o n survival for patients treated with \211 9 million units/week administered with and after intensive chemotherapy for >18 months or until progression; side effects reduce quality of life and the attraction of this therapy. Purine analogs: fludarabine has a response rate of 70% (38% CRs) in untreated patients and 50% (15% CRs) in previously treated patients. Responses to cladribine are similar for prev iously treated patients but less in de novo treatment and responses are less durable. Neith er convincingly improve disease free or overall survival. Fludarabine achieves responses in most patients with FL or SLL refractory to chlorambucil. Combinations of fludarabine with cyclophosphamide or with mitoxantrone (mitozantrone) and dexamethasone (FMD) increase respo nse rates and are widely used. Prophylaxis of P carinii by cotrimoxazole in all patients an d HZV by acyclovir in some is required during and for 6 months after therapy. Cellular bloo d products must be irradiated for 2 years after therapy. Monoclonal antibody therapy: 2 Rituximab (MabThera, Rituxan) is a humanized anti-CD20 monoc lonal antibody. As a single agent 375mg/m2 infusion weekly 4 weeks achieves a response rate 5 0% (6% CRs) in previously treated patients; median duration 13 months1. On relapse 40% will respond again. In newly diagnosed patients 4 further doses given over 9 months as main- te nance therapy enhances EFS (22 vs. 13 months). Toxicity is mild though there is a risk of a naphylaxis with the first course. Combination with chemotherapy enhances the response rate. In newly diagnosed patients: CHOP-R 100% responses, 66% CRs, >50% progression-free surviva l (PFS) with median follow up of 6 years. It has been used for \200\230in vivo purging \200\231 prior to stem cell harvest to improve the prospect of a PCR-negative harvest. In t he UK, NICE recommends its use in chemoresistant disease. 05-lymphoma.qxd 10.12.2003 04.13 PM Page 203 Lymphoma 2 Tositumomab, (Bexaar) a 131I-radiolabelled murine anti-CD20 mono- clonal antibody; beta a nd gamma emission; due to the targeted radia- tion a single infusion achieves higher respon se rates (97% OR and 76% CR in untreated patients; 74% OR & 30% CRs in treated patients) an d a higher response rate and more prolonged responses in advanced disease than the prior ch emotherapy had achieved; transient mild to moderate myelosuppression; antimurine antibodies develop especially in untreated patients. 203 2 Ipritumomab (Zevalin) a 90Yt-labeled murine anti-CD20 monoclonal antibody; beta emission only; also achieves superior response rates (80%) to rituximab in relapsed FL. Treatment of marginal zone lymphomas Gastric MALT lymphoma: eradication of H. pylori by 2 w eek course of clar- ithromycin, amoxicillin with omeprazole achieves CR in up to 80% of pat ients. Local radiotherapy or single agent chlorambucil can achieve CR in non-responders. No n-gastric MALT lymphomas: single agent chlorambucil, simple combination regimens or local r adiotherapy achieve good responses. Initial treatment of aggressive lymphomas Many patients can be cured by combination chemoth erapy or by radio- therapy. Localized DLBCL: patients with stage I and non-bulky stage II (mass <10 cm) disease without adverse prognostic factors treated with 3 cycles of CHOP followed by involved field radiot herapy (45 \200\22350Gy) achieve a 99% response rate 77% PFS and 85% long term survival. Th is is superior to radiotherapy alone (15% relapse in irradiation field) and to 8 cycles of CHOP. Advanced stage DLBCL: several chemotherapy regimens have curative potential. CR rates 50% t o >80%. Although CR rates to CHOP regimen have been bettered by some multi-agent regimens, long-term follow-up reveals comparable or inferior long-term PFS rates and greater treatmen t related toxicity. A prospective randomized trial comparing CHOP, m- BACOD, ProMACE-CytaBO M, and MACOP-B revealed no significant difference in response rates, time to treatment fail ure or survival. Several trials the superiority of any particular chemotherapy regimen for NHL. The CHOP regimen (p604) has been widely used because of ease of administration and rel ative tolerability. Some 30% of patients are cured using CHOP alone. The addition of Rituxi mab to CHOP improves responses and survival (see below).2 R-CHOP has been endorsed by NICE5 for use as first line therapy in CD20+ DLBCL stage II, III or IV. Evaluate response to the rapy after 3 \200\2234 courses and complete 6 courses if complete remission has been achiev ed. failed to demonstrate Consolidation therapy in DLBCL: in future different protocols may be appropriate for differ ent risk groups of patients (risk-adapted therapy). Consolidation of 1st CR by high dose th erapy and autologous SCT has 05-lymphoma.qxd 10.12.2003 04.13 PM Page 204 been examined in randomized trials. Improved DFS (and overall survival in one of three stud ies) was demonstrated for patients with \211 2 adverse factors on IPI. Further studies are in progress. It seems likely that a group of poor prognosis patients may benefit from inte nsive consolidation and the option should be discussed with eligible high risk patients in first remission. Monoclonal antibody therapy: rituximab produces responses in 30% relapsed DLBCL. More prom ising role in combination with initial chemotherapy: addition of Rituximab to CHOP initial therapy improved the CR rate (76% vs. 63%) and EFS (57% vs. 38%) and overall survival (70% vs. 57%) at 2 years with no added toxicity in a randomized study of 400 elderly patients wi th DLBCL2. Confirms Phase II data and further Phase III studies in progress has been endors ed by NICE5 R-CHOP for use as first line therapy for DLBCL. 204 Tositusimab: under examination in combination with BEAM high dose therapy to enhance tumor cell kill in autologous SCT for aggressive lymphoma. Mantle cell lymphoma: CHOP produces response rate 80% (CR 50%) with PFS <18 months and ov erall survival of 3 years and is not markedly different from results obtained with CVP. Reg imens such as fludarabine and cyclophosphamide can achieve further responses. Rituximab alo ne achieves response rate 35% (14% CR) with a median duration <1 year. Combination of ritu ximab with CHOP achieved a high rate of \200\230molecular remissions \200\231 as initial t herapy but a disappointing median PFS of 16 months. The combination of rituximab with sever al salvage regimens (e.g. FCM) improves responses. Relapsed patients with MCL who respond t o salvage therapy achieve further remissions with high dose therapy and autologous SCT but further relapse is usual. Rituximab pre-harvest acts as in vivo purge increasing the propor tion of PCR \200\223ve collections. High dose therapy and ASCT in first remission prolongs response duration and probably survival but is probably not curative3. Suitable patients w ith a sibling allogeneic SCT option should receive an allograft. Initial treatment of very aggressive lymphomas Non-endemic Burkitt lymphoma: successful tre atment of BL in children has informed adult treatment. High remission rates and long-term D FS achieved with intensive short duration (3 \200\2236 months) multi-agent chemotherapy reg imens including high dose methotrexate, high dose ifosfamide and CNS prophylaxis. Protocols cytarabine, etoposide, designed for lymphoblastic lymphoma or ALL clearly inferior to spec ific BL protocols. 90% EFS rates in childhood BL. Treatment of adults with BL with intensiv e regimens including intrathecal therapy such as CODOX- M/IVAC (Vincristine, doxorubicin, c yclophosphamide, methotrexate, folinic acid, G-CSF plus IT cytarabine and IT methotrexate/e toposide, ifosfamide, mesna, cytarabine, folinic acid, G-CSF plus IT methotrexate) improves response and survival rates ( 50% curable) though not to childhood results. The role of hi gh dose therapy is uncertain. Meningeal involvement still carries poor prognosis. Lymphoblastic lymphoma: management in adults has also followed more successful intensive re gimens in childhood based on ALL treatment 05-lymphoma.qxd 10.12.2003 04.13 PM Page 205 Lymphoma (including CNS prophylaxis). High CR rates ( 85%) and 5 year DFS up to 45% reported. The po or outlook for patients has led to evaluation of high-dose therapy with autologous or allog eneic BMT early in its management. Adult T-leukemia/lymphoma: (cid:9)p188. Salvage therapy in aggressive and very aggressive lymphoma Patients who relapse or fail to achieve remission with initial therapy have a poor prognosis. Without effective second-line (salvage) therapy, almost all die of progressive lymphoma in a median period of 3 \200\223 4 months. 205 Conventional chemotherapy: although relatively high CR rates have been reported with severa l salvage regimens, <10% patients with relapsed or refractory NHL will achieve long-term DF S. The addition of rituximab to EPOCH and ICE salvage regimens improves response rates. High dose therapy and SCT: high dose therapy (generally BEAM, BEAC or CBV) and autologous S CT is used to treat patients with relapsed or refractory aggressive or very aggressive NHL. A significant proportion of patients with DLBCL are cured (5 year EFS 46%; overall surviva l 53%) and its superiority to conventional dosage salvage therapy (5 year EFS 12%; overall survival 32%) was demonstrated in a randomized trial4. Best results are obtained when lymph oma still responsive to conventional dosage therapy and SCT performed in a state of minimal residual disease. HDT is generally preceded by 1-2 cycles of combination therapy e.g. mini - BEAM, DHAP, ESHAP with aim of testing chemo-responsiveness, inducing minimal residual dis ease and harvesting PBSCs. Syngeneic and allogeneic transplants have been used less frequen tly but are associated with cures. 1 McLaughlin, P. et al. (1998) Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J C lin Oncol, 16, 2825 \200\2232833 2 Coiffier, B. et al. (2002) CHOP chemotherapy plus rituxi mab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med, 346, 235 \200\223242 3 Vandenberghe, E. et al. (2003) Outcome of autologous transpl antation for mantle cell lymphoma: a study by the European Blood and Bone Marrow Transplant and Autologous Blood and Marrow Transplant Registries. Br J Haematol, 120, 793 \200\223800 . 4 Philip, T. et al. (1995) Autologous bone marrow transplantation as compared with salvag e chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin s lymphoma. N Engl J Med, 333, 1540 \200\2231545. 5 NICE Technology Appraisal 65, September 2003 05-lymphoma.qxd 10.12.2003 04.13 PM Page 206 CNS lymphoma Primary CNS lymphoma 2% of NHL cases; incidence increased partly by HIV pandemic; non-HIV r elated aged 55 \200\22370; commonly involves frontal lobes, corpus callosum or deep periven tricular structures; cognitive or personality change common; 10% seizures; 40% evidence of leptomeningeal spread; diagnosis by gadolinium-enhanced magnetic resonance and stereotactic needle biopsy; systemic lymphoma uncommon; poor prognosis improved by addition of systemic chemotherapy with high dose methotrexate to whole brain radiotherapy; improves survival wi th >95% responses and median survival 30 \200\22360 months; 50% relapse risk; most relapses in CNS, others mainly leptomeningeal and ocular, <10% systemic; delayed neurotoxicity comm on, esp. >60 years: dementia, ataxia, urinary dysfunction. 206 Secondary CNS lymphoma Usually meningeal involvement; occurs in up to 10% of cases of NHL; intrathecal methotrexat e, cytarabine and prednisolone twice weekly until CSF clear then weekly 6 cranial irr adiation as for ALL; insertion of Ommaya reservoir facilitates administration; simultanous systemic therapy including high dose methotrexate and cytarabine (penetrate CNS) normally n ecessary; poor prognosis; median survival <3 months. 05-lymphoma.qxd 10.12.2003 04.13 PM Page 207 Lymphoma 207 05-lymphoma.qxd 10.12.2003 04.13 PM Page 208 Hodgkin \200\231s lymphoma (Hodgkin \200\231s disease) First described by Thomas Hodgkin in 1832 the lineage of the neoplastic cells remained a su bject of debate for over 160 years. Micromanipulation of tissue sections followed by single cell PCR for Ig gene amplification demonstrates that the neoplastic cells in Hodgkin \200 \231s lymphoma (HL) are clonal B cells originating in a lymph node germinal center. HL is a germinal center-derived B-cell lymphoma. 208 Incidence 2 1% cancer registrations per annum. Annual incidence 3 per 100,000 in Europe and USA (less common in Japan). 2 Bimodal age incidence \200\224major peak between 20 and 29 years and minor peak 60 years. 2 Overall higher incidence in 9. 2 Nodular sclerosing (NS) histology is most common subtype in young adults (>75% of NS cases are <40 years) and peak at this age is con- fined to NS subtype and has a 3 preponderance. Risk factors 2 Associated with high socioeconomic status in childhood (esp. NS in young adults) and with Caucasian race in the USA. 2 Familial aggregations frequently reported: 99 4 risk in identical twins; 7 risk for siblings of young adults (no increase for sibs of older adults); ? genetic or environmental effect. 2 Considerable evidence linking EBV to HL: 4 risk of HL in individuals with a history of in fectious mononucleosis; EBV encoded nuclear RNAs detected in Reed-Sternberg (RS) cells; 26 \200\22350% cases +ve for EBV by molecular analysis (esp. mixed cellularity (MC) subtype). Histology and classification Immunological analysis has resulted in reclassification of HL in the REAL and WHO Classifications of Lymphoid Neoplasia ((cid:9)p195) into 2 major groups : Nodular lymphocyte-predominant HL (NLPHL): 3 \200\2238%; contains large atypical B cells an d lymphocytic and histiocytic (L&H) \200\230popcorn \200\231 cells. These cells are CD30 \200\223, CD15 \200\223, CD20+, CD45+, CD75+, CD79a+. \200\230Classical \200\231 HL: large mononuclear (Hodgkin \200\231s cells) or binucleate/m ultinuclear RS cells make up only 1 \200\2232% of the cellularity of the lymph node. These cells are CD30+ and typically CD15+, CD20 \200\223, CD45 \200\223, CD75 \200\223, CD79a \200\223. The predominant cells are an infiltrate of lymphocytes, plasma cells, eosinophils and histiocytes containing scattered neoplastic cells and a variable degree of fibrosis. Four histological subtypes: Nodular sclerosing HL (NSHL): 80%; prominent bands of fibrosis and nodular growth pattern; lacunar Hodgkin \200\231s cells; variable numbers of RS cells. 05-lymphoma.qxd 10.12.2003 04.13 PM Page 209 Lymphoma Mixed cellularity HL (MCHL): 17%; mixed infiltrate of lymphocytes, eosinophils and histioc ytes with classical RS cells. Lymphocyte depleted HL (LDHL): rare; diffuse hypocellular infiltrate with necrosis, fibrosi s and sheets of RS cells. Lymphocyte rich classical HL (LRCHL): uncommon; diffuse predominantly lymphoid infiltrate w ith scanty RS cells of \200\230classical \200\231 phenotype. 209 Clinical features 2 Presentation commonly with painless \200\230rubbery \200\231 supradiap hragmatic lymph node enlargement: frequently cervical gland(s). 2 Initial mode of spread occurs predictably to contiguous nodal chains. 2 Often involves su praclavicular and axillary glands and other sites. 2 Waldeyer \200\231s ring involvement is rare and suggests a diagnosis of NHL. 2 Lymphadenopathy in HL may wax and wane during obse rvation. 2 Spleen involved in 30% but palpable splenomegaly only in 10%, hepatomegaly 5%. 2 Abdominal lymphadenopathy is unusual without splenic involvement. 2 Supradiaphragmatic di sease intra-abdominal involvement is usual, and regional disease limited to subdiaphragm atic sites is uncommon (except NLPHL). 2 Bulky mediastinal and hilar lymphadenopathy may produce local symp- toms (e.g. bronchial or SVC compression) or direct extension (e.g. to lung, pericardium, pleura or rib). Pleural effusions in 20%. 2 Extranodal spread may also occur via bloodstream (e.g. to bone marrow (1 \200\2234%), lung or liver). Presence of disseminated extranodal disease is gener ally accompanied by generalized lymphadenopathy and splenic involvement; usually a late eve nt. 2 33% patients have \211 1 associated constitutional \200\230B \200\231 symptoms at pre- sentation: weight loss >10% body weight during the previous 6 months, unexplained fever or drenching night sweats. \200\230B \200\231 symptoms correlate with disease extent, bulk an d prognosis. Further systemic symptoms associated with HD (but not \200\230B \200\231 symp toms) are generalized pruritus and alcohol-induced lymph node pain. 2 A defect in cellular immunity has been documented in patients with HL rendering them more susceptible to TB, fungal, protozoal and viral infections including P carinii and HZV. 2 NLPHL more frequent in 9 (2 \200\2233 ); median age 35 years; typically localized at pre sentation; usually cervical or inguinal; infrequent \200\230B \200\231 symptoms; late rela pses occur; increased risk of DLBCL; otherwise favorable prognosis; 10 year OS 80 \200\2239 0%. 2 NSHL occurs typically in young adults (median age 26) and has a good prognosis if stage I/II. 2 MCHL has a median age of 30 years and an intermediate prognosis. 2 LDHL is more common in older adults; has a relatively poor prognosis. 2 LRCHL 9>3; tendency to localized disease; favorable prognosis. 05-lymphoma.qxd 10.12.2003 04.13 PM Page 210 Investigation, diagnosis and staging 2 Document \200\230B \200\231 symptoms in history. 2 Document extent of nodal involvement by clinical examination. 2 Confirm diagnosis by biopsy : best histology from lymph node excision biopsy; image guided needle biopsy or even laparotomy, mediastinoscopy or mediastinotomy ma y be necessary to obtain a tissue diagnosis. 2 Clinical staging is now usual; routine staging laparotomy for \200\230patholog- ical sta ging \200\231 abandoned; useful only if result may substantially reduce treatment. 2 Clinical staging includes the initial biopsy site and all other abnormali- ties detected by non-invasive methods. 2 Pathological staging requires biopsy confirmation of abnormal sites. 2 FBC: may show norm ochromic normocytic anemia, reactive leucocy- 210 tosis, eosinophilia and/or a reactive mild thrombocytosis. 2 ESR/plasma viscosity; U&E; LFTs; urate; LDH. 2 CXR. 2 CT chest, abdomen and pelvis to def ine occult nodal and extranodal involvement. 2 Bone marrow trephine biopsy to exclude marrow involvement in patients with stage III/IV disease or B symptoms (not essential in stage IA/IIA disease); B M may show reactive features. 2 Isotope bone scan, MRI or PET scan may be necessary. 2 Biopsy of other suspicious sites m ay be necessary e.g. liver or bone. 2 Attempt semen cryopreservation in young males with ad vanced disease (often unsuccessful in those with \200\230B \200\231 symptoms). Ann Arbor staging classification (Cotswolds modification) The Ann Arbor staging classificat ion has strong prognostic value and is deter- mined by the number of lymph node regions (no t sites) involved and the presence or absence of \200\230B \200\231 symptoms. The Cotswold s modification reflects the use of modern imaging techniques, recognizes clinical and patho logical staging and clarifies differences in disease distribution and bulk. Stage I involvement of a single lymph node region or structure Stage II involvement of two or more lymph node regions on the same side of the diaphragm (number of anatomical sites indicated by a subscript, e.g. II3). Stage III involvement of lymph node regions or structures on both sides of the diaphragm III1 involvement of spleen, splenic hilar, coeliac or portal nodes; III2 with involvemen t of para-aortic, iliac or mesenteric nodes Stage IV involvement of one or more extranodal sites (e.g. BM, liver or other extranodal sites no t contiguous with LN \200\224cf. \200\230E \200\231 below). A B absence of constitutional symptoms fever, weight loss >10% in 6 months or drenching night s weats Additional subscripts applicable to any disease stage: bulky disease (widening of med iastinum by >33% or mass >10cm) involvement of a single extranodal site contiguous or proxi mal to known nodal site. clinical stage pathological stage X E CS PS 05-lymphoma.qxd 10.12.2003 04.13 PM Page 211 Lymphoma Clinical imaging criteria 2 Lymph node involvement: >1cm on CT scan is considered abnormal. 2 Spleen involvement: splenomegaly may be \200\230reactive \200\231; filling defects on CT or USS confirm involvement. 2 Liver involvement: hepatomegaly insufficient; filling defect on imaging and abnormal LFTs confirm involvement. 2 Bulky disease: \211 10cm in largest dimension or mediastinal mass greater 211 than one third the maximal intrathoracic diameter. Initial therapy 2 Aim of treatment is to provide each patient with the best probability of cure while minimizing early and late treatment-related morbidity. 2 Best strategy is determined by tumor-related and patient-related factors. 2 Clinical trials remain necessary to evaluate therapeutic regimens in order to achieve thi s objective. BNLI/UKLG coordinate nationwide multicentre studies in UK. Early stage HL Prognostic factors: patients with stage I or II disease are generally divide d into favorable and unfavorable prognostic groups using risk factors, e.g. 2 Age >40. 2 ES R >50mm/h or >30 in presence of \200\230B \200\231 symptoms. 2 \211 4 separate sites of n odal involvement; mediastinal mass ratio > 0.35. 2 Other risk factors identified in studies have been gender, histology, disease confined to upper cervical nodes, anemia and low seru m albumin. Favorable prognosis: stage I or II HL without any risk factors Aim: cure with minimal side effects. 2 Treatment of choice is combined modality treatment, using attenuated duration ch emotherapy, e.g. ABVD 4 cycles + involved field radio- therapy (36 \200\22340Gy). 2 Aims to eliminate local disease and treat occult disease with reduced toxicity using limited field and attenuated number of cycles of chemotherapy. 2 Expected outcome: 90% failure-free survival (FFS) and >95% OS at 5 years. Alternative therapeutic options: Subtotal lymphoid irradiation (36 \200\22340Gy) offers 80 % FFS and >90% OS. It has been argued that most patients relapsing after radiotherapy alone can be salvaged by chemotherapy (e.g. ABVD) thus sparing most patients the toxicity of com bined modality therapy. However, long term toxicity from extended field radiotherapy is sig nificant. or EBVP 6 plus involved field radiotherapy (36 \200\22340Gy). 05-lymphoma.qxd 10.12.2003 04.13 PM Page 212 A very favorable subgroup (stage I, age <40, no \200\230B \200\231 symptoms, ESR <50, 3 an d MT ratio <0.35) may achieve 65 \200\22375% FFS and >90% OS at 10 years following extended field radiotherapy treatment alone. Patients with non-bulky NLPHL presenting with unilateral high cervical or epitrochlear lymp hadenopathy may be treated with involved field radiotherapy alone; at median follow up >7 y ears, more patients with NLPHL and LRCHL die of treatment-related toxicity than recurrent H L; may be best treated with limited dose, limited field radiotherapy alone; with similar ai m of reduced toxicity anti-CD20 antibody treatment may prove useful in NLPHL. Stage IA patients with subdiaphragmatic disease should receive chemotherapy field radiot herapy to avoid extended pelvic/abdominal fields that are myeloablative and sterilizing in women; patients with NLPHL localized to inguinal or femoral region may receive regional irr adiation only. 212 involved Unfavorable prognosis: stage I or II HL with any risk factors Aim: cure with some acceptabl e side effects. 2 Combined modality treatment essential, e.g. ABVD 6 cycles + involved field radiotherapy (36 \200\22340Gy). 2 Expected outcome: >85% DFS and 90% OS at 5 years. 2 Alternative therapeutic option: MOPP -ABV 6 cycles + involved field radiotherapy (36 \200\22340Gy). Advanced stage HL Prognostic factors: a prognostic score has been devised by the International Prognostic Fac tors Project1 for patients with advanced HL. Seven factors were identified: 2 Hb <10.5g/dL. 2 9 gender. 2 Stage IV. 2 Age \211 45. 2 WBC >16 109/L. 2 Lymphopenia <0.6 109/L or <8% of differential. 2 Albumin <40g/L. Patients with no adverse factors had 5 year failure-free progression of 84%. Each additiona l factor reduces 5 year failure-free progression by 7% until the group with 4 \200\2237 fa ctors have 40% failure-free progression at 5 years. Combination chemotherapy 2 Enter patient in a multicentre randomized clinical trial if poss ible. 2 ABVD ((cid:9)p596) is the standard regimen for patients with advanced HL (stage III or IV) not enrolled in a clinical trial. 2 In a randomized trial of 361 patients 6 \200\2238 cycles of ABVD was equiva- lent to 12 c ycles of MOPP-ABVD alternating regimen (CR 82% vs. 83%; FFS at 5 years 61% vs. 65%) and sup erior to 6 \200\2238 cycles of MOPP (CR 67%; 5 year FFS 50%)2. 2 ABVD has a much lower risk of infertility than MOPP regimens and is not associated with i ncreased risk of leukemia but the anthracycline 05-lymphoma.qxd 10.12.2003 04.13 PM Page 213 Lymphoma component may exacerbate the cardiac and pulmonary complications of mediastinal irradiation . 2 Often poorly tolerated by elderly patients due to cumulative doses of doxorubicin and bleomycin. 2 Alternative: brief duration dose intensified regimens, e.g. Stanford V low cumulative doses of alkylators, doxorubicin and bleomycin over 12 weeks followed by rad iotherapy to sites of bulk disease ( \211 5cm); FFS 89%, OS 96% at 6 years in a single inst itution study; multicentre ran- domised trials in progress; fertility preserved in a high p roportion; very low risk of leukemia. 213 Adjuvant radiotherapy Involved field radiotherapy is frequently give to bulky mediastinal d isease after completion of combination chemotherapy. This improves DFS but has no effect on OS. Meta-analysis suggest an overall 11% improvement in DFS and that the benefits are grea test for NSHL histology (least for MCHL and LDHL), for mediastinal bulk rather than other b ulky sites and that no benefit is gained in stage IV disease3. Late toxicity is increased. The lack of difference in overall survival was attributed to a greater number of second mal ignancies and poorer response and survival after relapse among patients who received combin ed modality therapy. Evaluation of response 2 Evaluate by physical examination and repetition of abnormal invest iga- tions at initial staging. 2 Often performed after 3 \200\2234 courses of chemotherapy to ensure ade- quate response and to determine total duration of treatment. 2 Residual masses sometimes present at completion of therapy, notably in mediastinum: may b e residual fibrotic tissue with no viable tumor. 2 If residual mass evident on CT, gallium scintigraphy, MRI or PET scan may exclude active disease if negative and obviate need for i nvasive biopsy. Cotswolds criteria: CR: complete resolution of all radiological and laboratory evidence of active HL. \200\230unce rtain CR \200\231, identifies the presence of a residual mass that remains stable or regres ses on follow-up. CRu: Salvage therapy 2 >50% of patients relapsing from primary radiotherapy of early stage HL may be cured by ABVD chemotherapy. 2 Durable FFP and prolonged survival are not generally achieved by con- ventional chemotherapy for patients relapsing after initial chemotherapy. 2 High-dose chemo therapy (BEAM or CBV) with autologous peripheral blood stem cell transplantation (SCT) has become the standard salvage approach for most pat ients relapsing after chemotherapy, producing high complete response rates (up to 80%), dur able complete remis- sions in 40 \200\22365% and low morbidity and mortality in selected pa tients. 05-lymphoma.qxd 10.12.2003 04.13 PM Page 214 2 HDT plus autologous SCT may be the best option for patients with refractory disease at in itial therapy though patients with progressive disease on conventional therapy still have a n unfavorable prognosis. 2 Allogeneic SCT has been performed in a small number of patients. Late complications of therapy 2 Treatment-induced sterility is frequently seen in 9 after t reatment with MOPP and MOPP-like regimens regardless of age (90% azoospermic 1 year after \211 6 co urses); the ABVD regimen produces significantly less infertility. Abnormal menstruation due to MOPP is more common in women over 30 (60 \200\22370%) and less common in those <20 (20 \200\22330%). 214 2 Premature menopause is more common after MOPP in older 3. 2 ABVD + mantle radiotherapy ca uses higher incidence of post-irradia- tion paramediastinal fibrosis causing persistent effort dyspnoea. 2 Patients cured of HL ar e at 4 risk of a second malignancy with a rela- tive risk of 6.4. 2 Solid tumors (commonly breast, lung, melanoma, soft tissue sarcoma, stomach and thyroid) comprise >50% of second malignancies; propor- tion increases as follow-up lengthens; risk 13% at 15 years and 22% at 25 years; associated with radiotherapy and young age at time of treatment; 75% occur within radiation fields. 2 Acute myeloblastic leukemia risk 3% at 10 years after treatment; peak incidence between 5 \200\2239 years; risk 5 10 years after therapy; par- ticularly ass ociated with MOPP chemotherapy and age >40 and radio- therapy dose >30Gy to mediastinum; ri sk 10 years after ABVD <1%. 2 NHL risk 7%; rises beyond 10 years and declines after 15 years; no clear association with type of therapy. 2 Cardiac toxicity: myocardial infarction, radiation-induced pericarditis, valvular disease and congestive failure occur at an increased frequency in patients previou sly treated for HL; higher risk in patients <40 at treatment. 2 Pulmonary toxicity: generally mild, usually asymptomatic changes in pulmonary function; a ssociated with mediastinal irradiation and bleomycin containing chemotherapy (ABVD). 2 Thyroid toxicity: 50% risk at 20 years after radiation to the neck and upper mediastinum; risk highest for ages 15 \200\22325; usually hypothy- roidism, minority develop hyperthyro idism, Hashimoto \200\231s thyroiditis, nodules or thyroid cancer. 2 Patients treated with HDT and autologous SCT have an increased inci- dence of myelodyspla sia and AML and azoospermia in males and pre- mature ovarian failure in females is usual. 1 Hasenclever, D. & Diehl, V. (1998) A prognostic score for advanced Hodgkin s disease. Int ernational Prognostic Factors Project on Advanced Hodgkin s Disease. N Engl J Med, 339, 150 6 \200\2231514 2 Canellos, G.P. et al. (1992) Chemotherapy of advanced Hodgkin s disease wi th MOPP, ABVD, or MOPP alternating with ABVD. N Engl J Med, 327, 1478 \200\2231484 3 Loeffl er, M. et al. (1998) Meta-analysis of chemotherapy versus combined modality treatment trial s in Hodgkin s disease. International Database on Hodgkin s Disease Overview Study Group. J Clin Oncol, 16, 818 \200\223829. 05-lymphoma.qxd 10.12.2003 04.13 PM Page 215 Lymphoma 215 05-lymphoma.qxd 10.12.2003 04.13 PM Page 216 This page intentionally left blank 216 06-MDS.qxd 10.12.2003 04.14 PM Page 217 Myelodysplasia 6 Myelodysplastic syndromes (MDS) 218 Classification systems 220 Clinical features of MDS 224 Prognostic factors in MDS 226 Clin ical variants of MDS 228 Management of MDS 230 Myelodysplastic/myeloproliferative diseases (MD S/MPD) 234 06-MDS.qxd 10.12.2003 04.14 PM Page 218 Myelodysplastic syndromes (MDS) The myelodysplastic syndromes (MDS) are a group of biologically and clinically heterogeneou s clonal disorders characterized by ineffective haematopoiesis and peripheral cytopenia due to increased apoptosis and by a variable tendency to evolve to acute myeloblastic leukemia . Incidence Predominantly affects elderly but may occur at any age; median age 69; annual inc idence 4/100,000 in general population; rising from 0.5/100,000 aged <50 years to 89/100,00 0 aged \211 80 years. Risk factors 2 Age. 2 Prior cancer therapy: notably with radiotherapy, alkylating agents 218 (chlorambucil, cyclophosphamide, melphalan; peak 4 \200\22310 years after therapy) or epipo dophyllotoxins (etoposide, teniposide; peak within 5 years). Note: prolonged alkylator ther apy used in rheumatology and other specialties. 2 Environmental toxins: notably benzene and other organic solvents; related to intensity and duration of exposure; also smoking, petroleum products, fertilizer s, semi-metal, stone dusts and cereal dusts. 2 Genetic: rare familial syndromes; MDS increa sed in children with Schwachman \200\223Diamond syndrome, Fanconi anemia and neurofibro- matosis type 1. Pathophysiology 2 Clonal haematopoietic stem cell disorder characterized by stepwise genetic progression possibly due to a combination of genetic predispo- sition and environme ntal exposures. 2 Abnormalities in the marrow microenvironment described: e.g. aber- rant cytokine production (increased inhibitory pro-apoptotic cytokines including TNF-a, IL- 6, TGF-b, IFN-g and Fas ligand) and altered stem cell adhesion. 2 MDS marrow stem cells display lowered apoptotic threshold to TNF-a, IFN-g & anti-Fas anti bodies and less response to haemopoietic growth factors. 2 Early indolent pro-apoptotic MDS transforms to aggressive prolifera- tive MDS as genetic lesions accumulate (ras, FLT3, FMS and p53 muta- tions associated with disease progression) . 2 Symptoms relate not only to the degree of cytopenia but to impaired function of granulocytes and platelets and may occur at near-normal or normal levels. 06-MDS.qxd 10.12.2003 04.14 PM Page 219 Myelodysplasia 219 06-MDS.qxd 10.12.2003 04.14 PM Page 220 Classification systems French \200\223American \200\223British (FAB) system 2 Morphology based classification wide ly adopted since 1982. 2 Defines five subtypes. 2 Requires dysplastic changes in \211 2 l ineages. 2 Useful for predicting prognosis and risk of evolution to acute leukemia. FAB classification Refractory anemia (RA): cytopenia of one peripheral blood (PB) lineage; normo- or hypercellular marrow with dysplasia \211 2 lineages; <1% PB blasts; <5% BM blast s. 25% of patients. 220