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 Refractory anemia with ringed sideroblasts (RARS): defined as for RA plus ringed sideroblas ts account for >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 ( >1 109/L); <5% PB blasts; \211 20% BM blasts; 10% of patients1. World Health Organization (WHO) system 2 Proposed reclassification of MDS based on morpholo gy, karyotype and clinical features; not yet universally accepted. 2 Lower threshold for diagnosis of AML from 30%720% blasts in PB or BM; eliminates FAB category \200\230RAEB-t \200\231. 2 Refined definitions for low grade MDS: RA and RARS. 2 Addition of new category \200\230r efractory cytopenia with multilineage dys- plasia \200\231 (RCMD). 2 Defines two subtypes of RAEB: RAEB-1 (5 \200\2239% BM blasts) and RAEB-2 (10 \200\22319% BM blasts) reflecting worse clinical outcomes with \211 10% blasts. 2 Recognizes the \200\2305q \200\223 syndrome \200\231 as a distinct narrowly defined enti ty. 2 Removes CMML to a newly created disease group: MDS/MPD. 06-MDS.qxd 10.12.2003 04.14 PM Page 221 Myelodysplasia WHO Classification System Condition PB findings BM Findings Refractory anemia (RA) anemia >6 months no or rare blasts erythroid dysplasia only <5% blasts <15% ringed sideroblasts Refractory anemia with ringed sideroblasts (RARS) anemia >6 months no blasts erythroid dysplasia only \211 15% ringed sideroblasts <5% blasts 221 Refractory cytopenia with cytopenias (bi- or pan-) multilineage dysplasia (RCMD) dysplasia in \211 10% cells in \211 2 myeloid cell lines <5%blasts no Auer rods <15% ring ed sideroblasts no or rare blasts no Auer rods <1 109/L monocytes Refractory cytopenia with cytopenias (bi- or pan-) multilineage dysplasia and no or rare bl asts ringed sideroblasts (RCMD-RS) dysplasia in \211 10% cells in \211 2 myeloid cell lines \211 15% ringed sideroblasts <5 % blasts no Auer rods no Auer rods <1 109/L monocytes Refractory anemia with excess blasts (RAEB-1) cytopenias <5% blasts no Auer rods <1 109/L monocytes unilineage or multilineage dysplasia 5 \200\2239% blasts no Auer rods Refractory anemia with excess blasts (RAEB-2) cytopenias 5 \200\22319% blasts Auer rods <1 109/L monocytes unilineage or multilineage dysplasia 10 \200\22319% blasts Auer rods Myelodysplastic syndrome, cytopenias unclassified (MDS-U) unilineage dysplasia in granulocytes or megakaryocytes <5% blasts no Auer rods no or rare blasts no Auer rods MDS associated with isolated del(5q) anemia <5% blasts platelets normal or 4 normal to increased megakaryocytes with hypolobated nuclei <5% blasts no Auer rods isolated del(5q) Vardiman, J.W. et al. (2002) The World Health Organization (WHO) classification of the myel oid neoplasms. Blood, 100, 2292 \200\2232302.