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) Table 5.9 Ann Arbor staging classifi cation (Cotswolds modifi cation) Involvement of a single lymph node (LN) region/structure (e.g. spleen, thymus, Waldeyer \200\231s ring) or single extranodal site (IE) Involvement of 2 or more LN regions on the s ame side of the diaphragm; localized involvement of 1 extranodal organ/ site and LN region on same side of diaphragm (IIE); number of anatomical sites can be indicated by a subscript , e.g. II3 Involvement of LN regions/structures on both sides of the diaphragm, which may a lso be accompanied by localized involvement of an extranodal organ/site (IIIE), involvement of spleen (IIIS) or both (IIISE) Diff use involvement of one or more extranodal sites (e.g . BM, liver, or other extranodal sites not contiguous with LN \200\224cf. \200\230E \200 \231 below). Stage I Stage II Stage III Stage IV A Absence of constitutional symptoms (B symptoms) Fevers >38oC, weight loss >10% in 6 months or drenching night sweats B Additional subscripts at any disease stage: X Bulky disease (widening of mediastinum by >33% or mass \211 10cm) E Involvement of a single extranodal site contiguous or proximal to known nodal site. Clinical imaging criteria \200 Lymph node involvement: >1cm on CT scan is considered abno rmal. \200 Spleen involvement: splenomegaly may be \200\230reactive \200\231; fi lling d efects on CT or USS confi rm involvement. PET/CT useful. Liver involvement: hepatomegaly insuffi cient; fi lling defect on imaging and abnormal LFTs confi rm involvement. PET/CT useful. Bulky disease: \211 10cm in largest dimension or mediastinal mass >1/3 the maximal intrathoracic diameter. FDG-PET scanning in HL \200 PET/CT scanning has become routine practice: higher sensitivi ty (>80%) and specifi city (790%); The stage is altered in 15 \200\22320% and treatment alt ered in 5 \200\22310%.2 (See Fig. 5.2). PET scanning has a clear role in restaging after therapy completed, particularly if CT shows residual mass(es). High \210\222ve predictive value (NPV; 785%). Lower +ve predictive value (PPV; 765%). PET scan after 2 cycles of chemotherapy ( \200\230early PET scan \200\231) may be predictive of DFS and OS with PPV 69% and NPV 95% in one study.2 Another study of PET after 2 cycles found 2-year PFS of 95% for PET \210\222ve patients vs 12.8% for PET+.3 218 CHAPTER 5 Lymphoma A role for CT defi nitely remains, though inferior in assessment of patients with apparent incomplete resolution of, usually previously bulky, nodal sites afte r therapy. PET is more accurate than CT for response assessment (780% vs 50%). False +ves: due to infl ammation, infection, granulomatous disease, brown fat, thymic hyper plasia in HL, marrow and splenic hyperplasia after G-CSF, previous radiotherapy. Delay of a t least 3 weeks after chemotherapy and 8 \200\22312 weeks after radiotherapy recommended. False \210\222ves: due to lesions below scanner resolution (5 \200\22310mm), too brief an interval between injection and scan (2h recommended), masking of tumor by physiological upt ake by brain, heart, or GI tract, hypergly- caemia reducing uptake by tumor. Fig. 5.2 PET and CT scans in patient with nodular sclerosing Hodgkin lymphoma demonstrating active disease (moderate FDG uptake on PET) in residual anterior mediastinal mass on CT af ter ABVD chemotherapy (see E color plate section). References 1. Hjalgrim, H. et al. (2003). Characteristics of Hodgkin \200\231s lymphoma aft er infectious mononucleosis. N Engl J Med, 349, 1324 \200\22332. 2. Seam, P. et al. (2007). The role of FDG-PET scans in patients with lymphoma. Blood, 110, 3507 \200\22316. 3. Hutchings, M. et al. (2006). FDG-PET after two cycles of chemotherapy predicts treatment failure and progression-free survival in Hodgkin lymphoma. Blood, 107, 52 \200\2239. 219 HODGKIN LYMPHOMA (HL) 220 CHAPTER 5 Lymphoma Treatment of HL Clinical trial entry where possible \200 Treatment results for HL have improved dramatica lly over the last 4 decades and a patient aged <60 years now has a >80% prospect of cure. \200 The aim of \200\230risk-adapted therapy \200\231 is to provide each patient with the best probability of cure while minimizing early and late treatment- related morbidity. Treatment is determined by stage, symptoms, disease bulk, and patient characteristics such as age and comorbidities. Clinical trials remain essential to evaluate therapeutic regimens in order to achieve this objective for all patients without over-treatment. \200 Patients wi th classical HL are generally divided into 3 treatment groups: early favorable, early unfavorable (intermediate), and advanced stage. Therapy of stage I/I I NLPHL refl ects its indolent nature. Prognostic factors Prognostic factors for patients with stage I/II HL that identify favor- able and unfavorable groups have been identifi ed by French and German study groups and def i ne treatment groups and these are now widely applied in Europe to inform treatment choice . There are small diff erences in the risk factors identifi ed and treatment groups defi ne d (GHSG adds IIB with large mediastinal mass or extranodal disease to the advanced stage gr oup1)1. In the USA, a similar approach is adopted using B symptoms and bulky disease to ide ntify patients who require more therapy: NCCN guidelines recommend that non-bulky stage I/I I B HL are treated like stage III/IV HL.2 (See Table 5.10.) Table 5.10 European study group risk factors and treatment groups in Hodgkin lymphoma EORTC/GELA GHSG A. Large mediastinal massa A. Large mediastinal massa Risk factors (RF) B. Age \211 50 years C. Elevated ESRb B. Extranodal disease C. Elevated ESRb D. \211 4 involved regions D. \211 3 involved regions Treatment groups NLPHL Supradiaphragmatic CS I/ II; no RFs CS I/II; no RFs Early stage favorable Supradiaphragmatic CS I/ CS I/II; no RFs II; no RFs Supradiaphragmatic CS I/ II; with \211 1 RF CS I, CSIIA with \211 1 RF; CS IIB with RF C/D but not RF A/B Early stage unfavorable (Intermediate) Advanced stage CS III/IV CS IIB with RF A/B; CS III/IV EORTC, European Organization for Research and Treatment of Cancer; GELA, Groupe d \200\231E tude des Lymphomes de l \200\231Adulte; GHSG, German Hodgkins Study Group. a Mediastinal ma ss ratio >0.35 (mass \211 10cm widely applied); b ESR >50mm/h or >30 in presence of \200 \230B \200\231 symptoms. 221 TREATMENT OF HL International Prognostic Score (IPS), Hasenclever score For advanced HL (stage III/IV) has been developed to distinguish patients who may be cured by conventional therapy from those who require more intensive therapy.3 7 unfavorable factors are combined into a simple progn ostic score predictive of 5-year FFP and OS (Table 5.11): \200 Serum albumin <40g/L \200 Hb <105g/L \200 Male gender \200 Stage IV disease \200 Age \211 45 years \200 WB C \211 15 \227 109/L \200 Lymphopenia <0.6 \227 109/L or <8% of diff erential. Patient s with no adverse factors have an 84% 5-year FFP. Each additional factor reduced FFP by 77% until patients with 4 \200\2237 factors have 747% -5 year FFP. Table 5.11 International Prognostic Score (IPS) for advanced HL Number of factors % of patients 5-year FFP (%) 5-year OS (%) 0 \200\2231 29 79 90 2 29 67 81 3 23 60 78 4 \200\2237 19 47 59 Classical HL, favorable stage I/II: no risk factors About 30% of patients have early stage favorable HL (stage IA/IIA) at presentation. The aim of treatment is cure with minimal side eff ects. Expected outcome: >90% FFS and >95% OS at 5 years. Treatment of choice ABVD 2 \200\2234 cycles IFRT. Historically combined modality treatme nt with abbreviated chemotherapy, usually ABVD \227 2 \200\2234 cycles and IFRT (20 \200 \223 30Gy) to sites of disease was used. This strategy is still followed by many centers. H owever, due to high cure rates with chemotherapy alone the risk of long-term complications has to be minimized and the role of radi- otherapy in younger patients is more and more unc ertain. Studies have showed no signifi cant diff erence in 5-year FFP and OS between ABVD \227 6 and combined modality treatment.4 In young patients 6 cycles of ABVD without IFRT ca n be considered. In patients PET \210\222ve post cycle 2, a total of 4 cycles can be consid ered. Alternative treatments used: Stanford V \227 8 weeks. Randomized trials continue to evaluate further reductions in treatment intensity seeking re duced toxicity by reduction of numbers of cycles, omission of bleomycin and dacarbazine, IF RT, or use of ABVD alone. The role of PET scans at 2 cycles to tailor further therapy is al so being examined (including escalation of treatment if early PET positive). 222 CHAPTER 5 Lymphoma ABVD often poorly tolerated by elderly patients due to cumulative doses of doxorubicin and bleomycin; G-CSF support may be necessary; pulmonary toxicity reported in 30% of patients, fatal in 72%.5 Restaging Early PET scanning is being adopted by many centers but the eviden ce regarding this is not conclusive. Trials continue to look at the value of early scanning (after 2 cycles). Interim scanning is currently recom- mended after cycle 4 to assess that patient is responding; earlier if clin- ical concern. Patients who fail to achieve complet e metabolic remission (CMR) on completion of therapy or have progressive disease should pro ceed to salvage therapy. Classical HL unfavorable stage I/II Aim of treatment is cure with acceptable side eff ects. Expected outcome: \200 785% DFS and 790% OS at 5 years. \200 715% will relapse within 5 years and 75% have 1 refractory disease. Treatment of choice ABVD \227 4 \200\2236 cycles + IFRT (bulky disease 30 \200\22336Gy; no n-bulky disease 20 \200\22330Gy) is widely used. However, due to high cure rates with chemo - therapy alone the risk of long-term complications has to be minimized and the role of rad iotherapy is more and more uncertain. IFRT is (gener- ally) recommended for bulky disease. Alternative treatments used: Stanford V \227 12 weeks; BEACOPP/ABVD. Clinical trials are continuing to evaluate the role of PET/CT scan in adjusting treatment a ccording to response, as well as more intensifi ed chemotherapy. Restaging Early PET scanning is being adopted by many centers but the evidence regarding th is is not conclusive. Trials continue to look at the value of early scanning (after 2 cycle s). Interim scanning is currently recom- mended after cycle 4 to assess that patient is res ponding; earlier if clin- ical concern. Patients who fail to achieve CMR on completion of t herapy or have progressive disease should proceed to salvage therapy. Classical HL advanced stage (III/IV) About 30% of patients have stage III/IV HL at presenta tion. Advanced stage HL has been curable with combination chemotherapy for >3 decades. Stan dard treatment is with ABVD.6 Treatment of choice ABVD \227 6 \200\2238 cycles. IFRT is (g enerally) recommended for bulky disease. Alternative treatments Stanford V, escalated BEACO PP. Restaging Interim scanning is currently recommended after cycle 4 to assess that patient is responding; earlier if clinical concern. Patients who fail to achieve CMR on completion of therapy or have progressive disease should proceed to salvage therapy. 223 TREATMENT OF HL Autologous SCT consolidation in \201 rst remission Not recommended. No advantage over sta ndard chemotherapy proven.7 Nodular lymphocyte predominant HL (NLPHL) Early stage non-bulky NLPHL \200 90% OS at 10 y ears. \200 Can be treated with IFRT alone; at median follow up >7 years, more die of treatment-related toxicity than recurrent HL. Observation after excision biopsy and rigorous staging may be appropriate in some patients. In some patients treatment as for classical HL is indicated. Stage III/IV NLPHL \200 96% CR and 74% FFS and 89% OS at 8 years. \200 Treatment identi cal to classical HL indicated.8 \200 Symptomatic patients not candidates for chemotherapy may benefi t from RT or single-agent rituximab. Evaluation of response \200 Restaging as outlined on E p.222. PET/CT is extremely useful. \200 The revised response criteria for lymphoma (E Table 5.8, p.209) are also used in HL with the added Cotswolds response criteria: \200 CR: complete resolution of all radiological and laboratory evidence of active HL. CRu: \200\230uncertain CR \200\231, identifi es presence of a residual mass that remains stable or regresses on follow-up. CMR is now used to interpret PET results. \200 The recommendations remain to restage afte r 4 courses of ABVD chemotherapy to ensure adequate response. The role of early-PET scannin g after cycle 2 is as yet unclear but this strategy has made its way into many a clinical p ractice already. If progressive disease at any restaging or <CRu or no CMR at the end of treatment, proceed to salvage treatment. Residual masses sometimes persist on CT at completion of therapy, notably in mediastinum: m ay be residual fi brotic tissue with no viable tumor. PET scan is the best method to exclud e active disease; if \210\222ve it obviates the need for invasive biopsy. Salvage therapy Durable FFP and prolonged survival not generally achieved by conven- tional chemotherapy for patients refractory to or relapsing after treat- ment. Salvage chemothera py followed by high dose therapy (HDT) and autologous SCT are indicated. Primary refractory HL (5 \200\22310%) \200 Low Karnofsky score, age >50 years and failure to achieve temporary remission to 1st line are adverse factors for OS.9 A MSKCC study showed that response to 2nd-line standard CT is predictive of response to HDT ( \211 25%PR 10-year EFS 60% vs 17% <25% PR).10 224 CHAPTER 5 Lymphoma Relapsed patients \200 10 \200\22330% will relapse, 90% within 2 years. Patients should u ndergo re-biopsy.2 Better EFS and PFS after HDT compared to salvage chemotherapy alone: up to 80% CR and >50% EFS after 3 years irrespective of duration of remission (BNLI11 and GHSG11). Salvage chemotherapy and HDT \200 Many schedules used; no consensus on best schedule, no regimen clearly superior. Most important is to achieve CR and for patient to go on to HDT and autol ogous SCT. Usually 2 cycles of chemotherapy prior to PBSCH. HDT most eff ective after CR ac hieved or with minimal residual disease. Schedules used: ChlVPP, DHAP, ESHAP, ICE, mini-BEAM, IGEV, (escalated) BEACOPP. HDT and autologous transplant: most commonly used schedules are BEAM or LEAM. Low morbidity and mortality (<5%) in selected patients. Patients who relapse after HDT have a poor prognosis and responses to further treatment are generally brief though median survival is 2 years. Patients ineligible for HDT: older age or co-morbidity: require individual- ized therapy: I FRT for localized relapse; palliative chemotherapy salvage. remission <12 months, B symptom s, and advanced stage are adverse factors for OS. Allogeneic SCT with standard conditioning: associated with higher early mortality; reduced intensity conditioning lowers risk and DLI can be eff ective, showing possible GVL eff ect. 12 Allogeneic transplant remains investigational. Brentuximab vedotin (SGN-35) Chimeric monoclonal antibody (targets the cell-membrane protei n CD30) linked to the antimitotic agent monomethyl auristatin E. 34% CR and 40% PR in refractory HL. Remissions often not sustained but can be used as bridg e to transplant. Accelerated FDA approval in 2011 and included on the UK national CDF list in 2013. Follow-up and monitoring for late complications2 \200 Clinical review and check FBC, ESR and chemistry every 3 months for 1 \200\2232 years, then every 6 months for 3 \200\2235 years. TSH annually if previous RT to neck. \200 Imaging not routinely indicated. \200 Annual infl uenza immunization especially after chest RT or bleomycin. \200 Early breast cancer screening: starting 5 \200\2238 years post-therapy or age 40 years if earlier. 225 TREATMENT OF HL Late complications of chemotherapy (both NHL and HL) 10 \200\22315 years after treatment th e risk of late complications of therapy exceeds the risk of relapse. Sterility: ABVD produces signifi cantly less infertility than other schedules used historic ally. Paramediastinal \201 brosis post RT: persistent eff ort dyspnoea. Second malignancy: note that the data included here is from the era when RT was used (much more) routinely; this i nformation has since led to change in practice. Included partly for historical purposes. \200 Solid tumors: commonly breast, lung, melanoma, soft tissue sarcoma, stomach, and thyroid; comprise >50% of 2nd malignancies. Risk 713% at 15 years and 722% at 25 years; associated with RT, dose, and volume and young age at time of treatment; 75% occu r within radiation fi elds; breast cancer occurs within 30 years of treatment in 30% of wom en treated with thoracic RT at age <30 years; lung cancer risk i 20 \227 in heavy smokers after thoracic RT for HL. Acute myeloblastic leukemia risk 73% at 10 years after treatment; peak incidence between 5 and 9 years; risk d10 years after therapy; particularly associated with older (and no longer used) MOPP chemotherapy (5% risk within 5 years), age >40 years and RT dose >30Gy to mediastinum; risk 10 years after ABVD alone <1%. NHL risk 7%; rises after 10 years and declines after 15 years; no clear association with type of therapy. Cardiac toxicity: mainly related to RT and chemotherapy agents (anthra- cyclin); higher ris k in patients <40 years at treatment; risk of coronary artery disease up to 6% at 10 years and 10 \200\22320% at 20 years. Pulmonary toxicity: generally mild, usually asymptomatic changes in pul- monary function; a ssociated with mediastinal irradiation and bleomycin containing chemotherapy (ABVD). Thyroid toxicity: 50% risk at 20 years after radiation to the neck and upper mediastinum; h ighest risk ages 15 \200\22325 years; usually hypothyroidism. Patients treated with HDT and autologous SCT: i incidence of myelodys- plasia and AML; azoospermia in males and pre-matu re ovarian failure in females is usual. References 1. Sasse, S. et al. (2006). Combined modality treatment for early stage Hodgkins lymphoma: the GHSG experience. Haematologica Reports, 2, 19 \200\22322. 2. NCCN Clinical Practice Guidelines in Oncology: Hodgkin Lymphoma. M www.nccn.org/ professionals/physician_gls/PDF/hodgkins.pdf 3. Hasenclever, D. and Diehl, V. (1998). A prognostic score for advanced Hodgkin \200\231s disease. International Prognostic Factors Project on Advanced Hodgkin \200\231s Disease. N Engl J Med, 339, 1506 \200\22314. 4. Straus, D.J. et al. (2004). Results of a prospective randomized clinical trial of doxoru bicin, bleomycin, vinblastine and dacarbazine (ABVD) followed by radiation therapy (RT) ver sus ABVD alone for stages I, II and IIA nonbulky Hodgkin disease. Blood, 104, 3483 \200\223 9. 5. Duggan, D.B. et al. (2003). Randomized comparison of ABVD and MOPP/ABV hybrid for the tr eatment of advanced Hodgkin \200\231s disease: report of an intergroup trial. J Clin Oncol, 21, 607 \200\22314. 226 CHAPTER 5 Lymphoma 6. Bonnadonna, G. and Santoro, A. (1982). ABVD chemotherapy in the treatment of Hodgkin \200\231s disease. Cancer Treatment Reviews, 9, 21 \200\22335. 7. Federico, M. et al. (2003). High-dose therapy and autologous stem cell transplantation versus conventional therapy for patients with advanced Hodgkin \200\231s lymphoma respondin g to front-line therapy. J Clin Oncol, 21, 2320 \200\2235. 8. Diehl, V. et al. (1999). Clinical presentation, course and prognostic factors in lymphoc yte- predominant Hodgkin \200\231s disease and lymphocyte-rich classical Hodgkin \200\231s disea se. J Clin Oncol, 17, 776 \200\22383. Josting, A. et al. (2000). Prognostic factors and tre atment outcome in primary progressive Hodgkin \200\231s lymphoma: a report from the German Hodgkin Lymphoma Study Group. Blood, 96, 1280 \200\2236. 9. 10. Moskowitz, C.H. et al. (2004). Eff ectiveness of high dose chemoradiotherapy and autologous stem cell transplantation for patients with biopsy-proven primary refractory Hod gkin \200\231s disease. Br J Haematol, 124, 645 \200\22352. 11. Linch, D.C. et al. (1993). Dose intensifi cation with autologous bone-marrow transplant ation in relapsed and resistant Hodgkin \200\231s disease: results of a BNLI randomized tri al. Lancet, 341, 1051 \200\2234. 12. Peggs, K.S. et al. (2005). Clinical evidence of a graft-versus-Hodgkin \200\231s lympho ma eff ect after reduced-intensity allogeneic transplantation. Lancet, 365, 1934 \200\22341. Further reading NCCN Clinical Practice Guidelines in Oncology: Hodgkin Lymphoma. M www.nccn .org/ professionals/physician _gls/PDF/hodgkins.pdf Seam, P. et al. (2007). The role of FDG -PET scans in patients with lymphoma. Blood, 110, 3507 \200\22316. Younes, A. et al. (2012) . Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin \200\231s lymphoma. J Clin Oncol, 30(18), 2183 \200\2239. 227 Chapter 6 Myelodysplasia Myelodysplastic syndromes (MDS) 228 Classifi cation of MDS 230 Clinical features of MDS 234 Prognostic factors in MDS 238 Clinical variants of MDS 242 Management of MDS 244 Response criteria 250 Myelodysplastic/myeloproliferative diseases (MDS/MPD) 252 228 CHAPTER 6 Myelodysplasia Myelodysplastic syndromes (MDS) The myelodysplastic syndromes (MDS) are a group of biologic ally and clinically heterogeneous clonal disorders characterized by ineff ective haematopoi esis and subsequent peripheral cytopenia. There is a vari- able tendency to evolve to BM fa ilure or acute myeloblastic leukemia, depending on the subtype. Incidence Predominantly aff ects the elderly but may occur at any age; median age 69; annua l incidence 4/100,000 in general population; rising from 0.5/100,000 aged <50 years to 89/1 00,000 aged \211 80 years. Risk factors \200 Age. \200 Prior cancer therapy: notably with radiotherapy, alkylating agents (chlorambucil, cyclophosphamide, melphalan; peak 4 \200\22310 years after therapy) or epipo dophyllotoxins (etoposide, teniposide; peak within 5 years). Note: prolonged alkylator therapy also used in other specialties (rheumatology). Prior autologous SCT (up to 20% of patients with NHL). \200 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. Genetic: rare familial syndromes; MDS i in children with congenital BM failure syndromes, S chwachman \200\223Diamond syndrome, Fanconi anemia, and neurofi bromatosis type 1. Pathophysiology \200 Clonal haematopoietic stem cell disorder characterized by genetic progression possibly due to a combination of genetic predisposition and environmental expos ures. Early mutations cause diff erentiation arrest and dysplasia with later mutations leading to proliferation, clonal expansion, and AML (variable). Recurring cytogenetic abnormalities well recognized but molecular pathogenesis and basis fo r progression remain largely undefi ned. \200 The MLL gene at 11q23 is up-regulated (with HOXA9 activation) in signifi cant % of MDS and AML patients including normal karyotypes.1 Abnormalities in the marrow microenvironment described: e.g. aberrant cytokine production (i inhibitory pro-apoptotic cytokines including TNF- , IL-6, TGF- , IFN- , and Fas ligand) and altered stem cell adhesion. MDS marrow stem cells display lowered apoptotic threshold to TNF- , IFN- , and anti-Fas antibodies and less response to haemopoietic growth factors. Early indolent pro-apoptotic MDS transforms to aggressive proliferative MDS as genetic lesions accumulate (ras, FLT3, FMS, and p53 mutations associat ed with disease progression). 229 MYELODYSPLASTIC SYNDROMES (MDS) Symptoms relate not only to the degree of cytopenia but to impaired function of granulocyte s and platelets and may occur at near normal levels. Reference 1. Poppe, B. et al. (2004). Expression analyzes identify MLL as a prominent targe t of 11q23 amplifi cation and support an etiologic role for MLL gain of function in myeloid malignanci es. Blood, 103, 229 \200\22335. 230 CHAPTER 6 Myelodysplasia Classi \201 cation of MDS The historical FAB classifi cation has largely been superseded b y the revised 2008 WHO classifi cation of MDS.1 The NCCN guidelines2 include the FAB classi fi cation for historical context, the same is done here. World Health Organization (WHO) system1 (See Table 6.1.) \200 Classifi cation of MDS base d on morphology, karyotype, and clinical features that defi nes subgroups and provides valu able prognostic information useful for clinical decision-making. Initially proposed in 2001 . Revised in 2008.1,3 \200\2236 Diagnosis of AML if \211 20% blasts in PB or BM (as opposed to the FAB classifi cation whi ch has a \200\230RAEB-t \200\231 category, which is acknowledged as a footnote to the WHO classifi cation). Defi nes 2 subtypes of RAEB: RAEB-1 (5 \200\2239% BM blasts) and RAEB-2 (10 \200\22319% BM blasts) refl ecting worse clinical outcomes with \211 10% blasts. A footnote to the classi fi cation acknowledges the RAEB-t category from the old FAB classifi cation. WHO defi nes t his as AML. \200 Recognizes the \200\2305q \210\222 syndrome \200\231 as a distinct narr owly defi ned entity. \200 Removed CMML to a newly created disease group: MDS/MPD. The 2008 revision included a new subtype, refractory cytopenia with unilineage dysplasia (R CUD). Unilineage dysplasia is accepted for diag- nosis provided it persists \211 6 months and other causes of dysplasia are excluded. Further subtyped in refractory anemia (RA), ref ractory neu- tropenia (RN), and refractory thrombocytopenia (RT). French \200\223American \200\223British (FAB) system \200 Its use has been superseded by WHO system. \200 Morphology-based classifi cation used since 1982.7 \200 Requires dyspl astic changes in \211 2 lineages. \200 Useful for predicting prognosis and risk of evolu tion to acute leukemia. FAB classi \201 cation \200 Refractory anemia (RA): cytopenia of 1 peripheral blood (PB) lineage; normo- or hypercellular marrow with dysplasia \211 2 lineages; <1% PB blasts; <5% BM blasts. 25% of patients. Refractory anemia with ringed sideroblasts (RARS): defi ned as for RA plus ringed siderobla sts constituting >15% nucleated erythroid cells; 15% of patients. Refractory anemia with excess blasts (RAEB): cytopenia of \211 2 PB lineages; dysplasia of all 3 BM lineages; <5% PB blasts; 5 \200\22320% BM blasts; 35% of patients. Refractory anemia with excess blasts in transformation (RAEB-t): cytopenia of \211 2 PB li neages; dysplasia of all 3 BM lineages; \211 5% PB blasts; 21 \200\22330% BM blasts or Aue r rods in blasts; 15% of patients. Chronic myelomonocytic leukemia (CMML): PB monocytosis (>1 \227 109/L); <5% PB blasts; \211 20% BM blasts; 10% of patients. 231 CLASSIFICATION OF MDS Table 6.1 WHO classifi cation system1 Condition PB \201 nding BM \201 ndings No or rare blasts 3 subtypes: \200 Refractory anemia Dyserythropoiesis, or Dysgranulopoiesis, or Dysmegakaryocytopoiesis only Refractory cytopenia with unilineage dysplasia (RCUD) (RA) Refractory neutropenia (RN) <5% blasts <15% ringed sideroblasts Refractory thrombocytopena (RT) Anemia No blasts \211 15% ringed sideroblasts erythroid dysplasia only <5% blasts Refractory anemia with ringed sideroblasts (RARS) Cytopenias (bi- or pan-) No or rare blasts No Auer rods <1 \227 109/L monocytes Dysplasia in \211 10% cells in \211 2 myeloid cell lines <5%blasts No Auer rods <15% ring ed sideroblasts Refractory cytopenia with multilineage dysplasia (RCMD) As RCMD As RCMB but with \211 15% ringed sideroblasts RCMD-RS Cytopenias <5% blasts No Auer rods <1 \227 109/L monocytes Unilineage or multilineage dysplasia 5 \200\2239% blasts No Auer rods Refractory anemia with excess blasts (RAEB-1) Cytopenias 5 \200\22319% blasts Auer rods <1 \227 109/L monocytes Unilineage or multilineage dysplasia 10 \200\22319% blasts Auer rods Refractory anemia with excess blasts (RAEB-2) Anemia <5% blasts Platelets n or i MDS with isolated del(5q) n to i megakaryocytes with hypolobated nuclei <5% blasts No Auer rods Isolated del(5q) Cytopenias Unilineage dysplasia or no dysplasia Characteristic MDS cytogenetics Blasts <5% MDS \200\224unclassifi ed (MDS-U) Reproduced from reference 1 with permission. Copyright American Society of Hematology. 232 CHAPTER 6 Myelodysplasia References 1. Swerdlow, S.H. et al. (2008). WHO Classifi cations of Tumors of Haematopoieti c and Lymphoid Tissues, 4th ed. Lyon: IARC. 2. NCCN (2014). NCCN Practice Guidelines in Oncology: Myelodysplastic Syndromes, V2.2014. Fort Washington, PA: NCCN. 3. Swerdlow, et al. (2008). WHO classifi cations of Tumors of Haematopoietic and Lymphoid Tissues, 4th ed. Lyon: IARC 3. Vardiman, J.W. et al. (2009). The 2008 revision of the World Health Organization (WHO) c lassifi cation of myeloid neoplasms and acute leukemia: rationale and important changes. Bl ood, 114, 937 \200\22351. 4. Germing, U. et al. (2000). Validation of the WHO proposals for a new classifi cation of primary myelodysplastic syndromes: a retrospective analysis of 1600 patients. Leukemia Res, 24, 983 \200\22392. 5. Malcovati, L. et al. (2005). Prognostic factors and life expectancy in myelodysplastic syndromes classifi ed according to WHO criteria: a basis for clinical decision making. J Cl in Oncol, 23, 7594 \200\223603. 6. Bowen, D. et al. (2006). Prospective validation of the WHO proposals for the classifi ca tion of myelodysplastic syndromes. Haematologica, 91, 1596 \200\223604. 7. Bennett, J.M. et al. (1982). Proposals for the classifi cation of the myelodysplastic sy ndromes. Br J Haematol, 51, 189 \200\22399. 233 CLASSIFICATION OF MDS 234 CHAPTER 6 Myelodysplasia Clinical features of MDS \200 Patient may be asymptomatic. Incidence i with age. \200 D iffi cult diagnosis in patient with multiple comorbidities where anemia of chronic disease is also in the diff erential diagnosis. \200 Presentation blood results range from mild a nemia to profound pancytopenia. \200 Macrocytic or normocytic anemia usual (60 \200\22380%). \200 neut ropenia (50 \200\22360%). \200 thrombocytopenia (40 \200\22360%). Isolated thrombocytopenia is an unusual presentation for MDS. \200 Symptoms of underlying cytopenias and cellular dysfunction may develop: \200 Anemia \200\224fatigue, shortness of breath, exacerbation of cardiac symptoms. Neutropenia and dysfunctional granulocytes \200\224recurrent infection. \200 Thrombocytop enia and dysfunctional platelets \200\224spontaneous bruising, purpura, bleeding gums. Constitutional symptoms including anorexia, weight loss, fevers, and sweats usually features of more \200\230advanced \200\231 subgroups. Splenomegaly/organomegaly is not seen in MDS. Investigation and diagnosis History: prior exposure to chemotherapy/radiation; FH of MDS/AM L; symptoms of anemia, recurrent infection, bleeding or bruising; timing, severity, and spe ed of onset of cytopenias; previous transfusion; medi- cation history and co-morbidities. Examination: pallor; infection; bruising. FBC: macrocytic/normocytic anemia neutropenia thrombocyto- penia thrombocytosis: \200 Hb <110g/L and/or \200 Neutrophilis <1.5 \227 109/L and/or \200 Platelets <100 \227 109/L. Blood \201 lm: essential. Morpholog ical dysplastic features: macrocytosis; dimorphic red cells; basophilic stippling in RBCs; dysplastic granulocytes: pseudo-Pelger forms (Fig. 6.1), hypersegmented neutrophils, hypogr an- ular neutrophils, dysmorphic monocytes blasts; platelets can be large or hypogranula r. Reticulocyte count: not i. U&E, LFTs, ECG, and CXR: no typical abnormalities; to assess co-mor- bidity. Serum ferritin, vitamin B12, and RBC folate: usually n levels; ferritin may be elevated in RARS/RCMD-RS.