04-leukemia.qxd 10.12.2003 04.12 PM Page 163 Leukemia Prognostic factors The most important prognostic factors are listed below. These are useful for risk stratification to identify patients who require transplantation in first CR. 2 Pa tient age (<50y CR >80%, LFS>30%; \211 50y CR <60%, LFS <20%) 2 High leucocyte count (>30 109/L in B precursor-ALL; >100 109/L in T-ALL) poor risk. 163 2 Immunophenotype: pro-B-ALL and pro-T-ALL have poorer outcomes; common pre-B-ALL still poo r; mature B-cell ALL and T-cell ALL had poorer outcomes before the use of more intensive re gimens, now better. 2 Cytogenetics: Ph+ very poor prognosis: <10% LFS after chemotherapy; for others ((cid:9)p159). 2 Long time to CR (>4 \200\2235 weeks) 2 High MRD level after induction (>10 \200\2233); pe rsistent/increasing MRD during consolidation. Management of relapse 2 Relapse rate is highest within the first 2 years but may occur afte r 7 years. 2 20% occur outside the bone marrow, generally CNS; testis and other sites occur in 5%. 2 Isolated extramedullary relapse is often followed by hematological relapse; these patients require local treatment followed by reinduction therapy. 2 Best predictive factor for response is duration of first CR (better >18 months). 2 With second-line regimens 50 \200\22360% of patients will achieve a short second CR (gene rally <6 months) and prompt BMT offers the only prospect of LFS and cure. 04-leukemia.qxd 10.12.2003 04.12 PM Page 164 Chronic myeloid leukemia (CML) Malignant tumor of an early haemopoietic progenitor cell. The clonal marker is found in all three myeloid lineages and in some B and T lympho- cytes demonstrating a primitive origin. Incidence Rare disease with a frequency of 1.25 per 100,000. Rare in children and median ag e of onset is 50 years with slight 9 excess. Irradiation is the only known epidemiological factor. Classification Classified as a myeloproliferative disorder ((cid:9)p238) with which it shar es a number of clinical features. However, it also has certain unique biological properties : 2 Characterized in >80% patients by the presence of the Philadelphia 164 chromosome (Ph). Reciprocal translocation between chromosomes 9 and 22, (t9;22)(q34;q11), i nvolving two genes, BCR and ABL that form a fusion gene BCR-ABL on chromosome 22. This prod uces an aberrant 210 kDa protein that has greater tyrosine kinase activity than the normal ABL protein. This gene is believed to play a role in the patho- genesis of CML but addition al genetic changes appear necessary. 2 10% of patients have variant translocations involving chromosome 22 9 and other chromo somes. A further 8% with typical clinical features lack the Ph chromosome, i.e. have Ph-neg ative CML; half of these have the hybrid BCR-ABL gene: Ph-negative, BCR-ABL-positive CML. Natural history 2 Biphasic or triphasic disease \200\224chronic phase, accelerated phase an d blast crisis; 50% transform directly from chronic phase to blast crisis. 2 >85% patients present in chronic phase. 2 Duration of chronic phase varies (typically 3 \200\2236 years; median 4.2 years). 2 Transformation is least likely in the 2 years immedia tely after diagnosis but occurs at an annual rate of 20 \200\22325% thereafter. 2 Accelerated phase characterized by blood counts and organomegaly becoming increasingly refractory to therapy; some have constitutional symptoms; generally b rief. 2 Blast crisis resembles acute leukemia with >20% blasts and promyelo- cytes in blood or marrow. Clinical symptoms and signs 2 30% asymptomatic at diagnosis; present after routine FBC. 2 F atigue, lethargy, weight loss, sweats. 2 Splenomegaly in >75%; may cause (L) hypochondrial pain, satiety and sensation of abdominal fullness. 2 Gout, bruising/bleeding, splenic infarction and occasionally priapism. 2 Signs include mo derate to large splenomegaly (40% >10cm), hepatomegaly (2%), lymphadenopathy unusual. 2 Occasional signs of leucostasis at presentati on. 04-leukemia.qxd 10.12.2003 04.12 PM Page 165 Leukemia Diagnosis and investigations 2 FBC and blood movie show 4 WBC (generally >25 109/L, ofte n 100 \200\223300 109/L): predominantly neutrophils and myelocytes; basophilia; sometime s eosinophilia. 2 Anemia common; platelets typically normal or 4. 2 Neutrophil alkaline phosphatase (NAP) s core and ESR 5 in absence of secondary infection. 2 LDH and urate levels 4. 2 Bone marrow shows marked hypercellularity due to myeloid hyper- 165 plasia (blasts <10% in chronic phase; >10% in accelerated phase; >20% blasts + promyelocyte s = blast crisis); trephine useful to assess marrow fibrosis. 2 Cytogenetic examination of blood or marrow for confirmatory t(9;22). Peripheral blood movie in CML: note large numbers of granulocytic cells at all stages of di fferentiation. Differential diagnosis Differentiate chronic phase CML from leukaemoid reaction due to infe c- tion, inflammation or carcinoma (NAP 4 or normal; absent Ph chromo- some) and CMML (abso lute monocytosis; trilineage myelodysplasia; absent Ph chromosome); 5% present with predomi nant thrombocytosis and must be differentiated from ET (NAP 4/normal; absent Ph chromosome) . Prognostic factors 2 Sokal score based on age, spleen size, platelet count and % blasts in blood can be used to identify good, moderate and poor prognosis groups; (see p685) 2 Response to IFN-a therapy is an important prognostic factor. Treatment of chronic phase 2 HLA-type patients aged <50 years and their sibs; 30% have a co mpat- ible sibling donor; if no compatible sibling and aged <40, perform pre- liminary MUD search to determine prospective donor availability. 2 Therapeutic decision making in chroni c phase is difficult: allogeneic transplantation is the only curative treatment; however, it carries sig- nificant morbidity and mortality and many patients find this a difficult 04-leukemia.qxd 10.12.2003 04.12 PM Page 166 option; it is vital that each patient is aware of treatment options and their risks and ben efits. 2 Leukapheresis should be performed with cryopreservation of stem cells which may be used for future autologous rescue if required; it may also be necessary for tr eatment of leucostasis or priapism. 2 Allopurinol should be commenced. 2 Hydroxyurea has been drug of choice for controlling WB C, \200\230normalizing \200\231 the FBC and reducing spleen size in chronic phase. Maintenance 1 \200\2231.5g PO od. No eff ect on cytogenetics or natural history. Side effects: rash, mouth ulcers and diarrhea. 2 Interferon-a (IFN-a) at a target dose of 5 million units/m2/day SC corrects hematological abnormalities in 75% and produces complete cytogenetic response (CCR) in 10 \200\22315% an d major cytogenetic response (MCR; <33% Ph+ cells) in 15 \200\22330%. 166 2 Treatment with IFN-a is associated with prolonged time to progression and longer survival (57% at 5 years), most significantly in those with com- plete and major responses; adding cytarabine increases CCRs to 25 \200\22335% and improves survival. 2 IFN-a side effects (malaise, febrile reactions, anorexia and weight loss, depression) red uce quality of life and not tolerable for many patients. 2 Polyethylene glycol-IFN administered once weekly and has a more favorable side effect profile. 2 Imatinib (Glivec \200\232) gives better cytogenetic responses and progression free surviv al with fewer side effects; has changed the therapeutic algorithm in CML; a small molecule signal transduction inhibitor that specifically targets BCR-ABL and some other tyrosine kin ases: \200\223 400mg PO od in newly diagnosed patients in chronic phase pro- duces complete hematological response in 96%, major cytogenetic response in 83% and complet e cytogenetic response in 68%; only 3% achieve a molecular remission (negative RT-PCR for B CR-ABL at 10 \200\2235 \200\22310 \200\2236). \200\223 Most patients achieve major cytogenetic response (MCR) within first 6 months of t herapy; patients with MCR have lower risk of relapse. \200\223 Commonest side effects are myelosuppression, oedema, nausea, muscle cramps, skin rash, fatigue, diarrhea, headache and arthralgia; most are mild to mode rate and easily manageable. \200\223 Now approved in both US by FDA, and in UK by NICE for not only IFN-a-resistant pa tients for all newly diagnosed patients.1 \200\223 Imatinib combined with IFN-a or cytarab ine are under examination. \200\223 Uncertainty about long term outcomes, resistance and r esponse duration. 2 Sibling-matched allogeneic stem cell transplant is treatment of choice for age <50 unless they develop a major cytogenetic response, but only 30% will have sibling match. Transplan t related mortality is approximately 20%. Outcomes best in younger patients (<30) in chroni c phase <1 year from diagnosis. RT-PCR for BCR-ABL is used to monitor minimal residual dise ase once Ph-negative engraftment is achieved. 1 www.nice.org.uk 04-leukemia.qxd 10.12.2003 04.12 PM Page 167 Leukemia 2 MUD allogeneic transplant, if available, should be used for <25 age group and considered <40 years but transplant related mortality rises up to 45%. 2 Non-myeloablat ive conditioning has been used to reduce treatment related toxicity in older patients using donor lymphocyte infusions to produce a graft-versus-leukemia (GvL) effect; it is too earl y to assess long term results. A treatment \200\230algorithm \200\231 2 A young patient (<40) with CML in chronic phase w ith a matched sibling 167 donor should probably still be allografted within 6 \200\22312 months of diagnosis but may prefer a trial of imatinib. 2 All other patients should receive imatinib (in the UK if fail to tolerate IFN- a); review BM cytogenetics at 6 months. 2 If BM <35% Ph-negative, alternatives should be discussed: i.e. increased Imatinib, trials of combination therapy or stem cell transplantation, if an option. 2 If BM \211 35% Ph-neg continue therapy as long as cytogenetics stable or improving (RT-PCR for BCR-ABL if CCR). 2 Monitor at least annually; if progression, discuss above options especially BMT. Complications 2 Modest increased infection risk \200\224sometimes atypical organisms. 2 Acc eleration to blast crisis (75% myeloid, 25% lymphoid). 2 Lymphoid blast crisis treatable wi th modified ALL protocol, may survive >12 months. 2 Myeloid blast crisis usually refractory to conventional chemotherapy, sur- vival 2 \200\2235 months. Prognosis Overall median survival with standard chemotherapy 5.5 years (range 3 months \200 \22322 years). Survival improvement with Imatinib not yet quantified. Sibling matched allog eneic transplant (all ages 5 year median survival 60%). MUD transplant (all ages \200\2245 year median survival 40%). Blast crisis overall median survival 6 months. Treatment of advanced phase CML 2 Accelerated phase patients on imatinib 600mg od have hema tological and cytogenetic responses, prolongation of time to progression and improved survi val. Eligible patients should receive an allograft. 2 Blast crisis CML responds to imatinib 600mg od in a high proportion of cases with less toxicity than chemotherapy but response duration is short and where possibl e an allograft should be performed. 2 Allogeneic BMT offers eligible patients with advanced phase CML the only prospect of prol onged survival and possible cure; results are significantly less good than for BMT in chron ic phase (0 \200\22310% 5 year survival in blast crisis) though achievement of second chron ic phase improves the results after blast crisis. 2 Relapse after allogeneic BMT has been successfully treated with donor lymphocyte infusion s (DLI) (60 \200\22380% response in molecular or cytoge- netic relapse); GvHD is a side eff ect but is less frequent with incre- mental doses of DLI. 04-leukemia.qxd 10.12.2003 04.12 PM Page 168 Chronic lymphocytic leukemia (B-CLL) Progressive accumulation of mature-appearing, functionally incompetent, long-lived B lympho cytes in peripheral blood, bone marrow, lymph nodes, spleen, liver and sometimes other orga ns. Incidence Commonest leukemia in Western adults (25 \200\22330% of all leukaemias). 2.5/100, 000 per annum. Predominantly disease of elderly (in over 70s, >20/100,000). Median age at d iagnosis 65 years. 9 : 3 ratio 2:1. Etiology Unknown. No causal relationship with radiation, chemicals or viruses. Small propor tion are familial. Genetic factors suggested by low incidence in Japanese even after emigra tion. Lymphocyte accumulation appears to result from defects in intracellular apoptotic pat hways: 90% of CLL cases have high levels of BCL-2 which blocks apoptosis. 168 Clinical features and presentation 2 Often asymptomatic; lymphocytosis (>5.0 109/L) on r outine FBC. 2 With more advanced disease: lymphadenopathy: painless, often symmet- rical, s plenomegaly (66%), hepatomegaly and ultimately BM failure due to infiltration causing anemi a, neutropenia and thrombocytopenia. 2 Recurrent infection due to acquired hypogammaglobuli naemia: esp. Herpes zoster. 2 Patients with advanced disease: weight loss, night sweats, general malaise. 2 Autoimmune phenomena occur; DAT +ve in 10 \200\22320% cases, warm anti- body AIHA in <50% these cases. Autoimmune thrombocytopenia in 1 \200\2232%. Diagnosis FBC: lymphocytosis >5.0 109/L; usually >20 109/L, occasionally >400 109/ L; anemia, thrombocytopenia and neutropenia absent in early stage CLL; autoimmune haemolysi s thrombocytopenia may occur at any stage. Blood movie: lymphocytosis with \200\230mature \200\231 appearance; characteristic artefac tual damage to cells in movie preparation produces numerous \200\230smear cells \200\231 ( Note: absence of smear cells should prompt review of diagnosis); spherocytes, polychromasia and 4 retics if AIHA; 5 platelets if BM failure or ITP. Blood movie in CLL: numerous \200\230mature \200\231 lymphocytes with smear cells. From Ox ford Textbook of Oncology, 2E, with permission. 04-leukemia.qxd 10.12.2003 04.12 PM Page 169 Leukemia Immunophenotyping: crucial to differentiation from other lymphocytoses ((cid:9)table p174). First line panel: CD2; CD5; CD19; CD23; FMC7; SmIg (k/l); CD22 or CD79b. CLL characteristi cally CD2 and FMC7 \200\223ve; CD5, CD19 and CD23 +ve; SmIg, CD22, CD79b weak; k or l ligh t chain restricted. Immunoglobulins: immuneparesis (hypogammaglobulinaemia) common; monoclonal paraprotein (usu ally IgM) <5%. 169 Bone marrow: >30% \200\230mature \200\231 lymphocytes. Trephine biopsy: provides prognostic information: infiltration may be nodular (favorable); interstitial; mixed; diffuse (unfavorable). Lymph node biopsy: rarely required; appearances of lymphocytic lymphoma. Cytogenetics: prognostic value; abnormalities in >80% using FISH: 13q \200\223 (55%), 11q \200\223 (18%), 12q+ (16%), 17p \200\223 (7%), 6q \200\223 (7%); 11q \200\223, 17q \200\223 very unfavorable; sole 13q \200\223 or 6q \200\223 favorable. Clonal evolution occurs over time. 11q \200\223 and 17q \200\223 associated with advanced disease. FISH showing trisomy 12 (three bright spots in each nucleus, each of which repre- sents chr omosome 12). From Oxford Textbook of Oncology, 2E, with permission. Other tests: U&E; LFTs; LDH; b2-microglobulin; imaging as necessary for symptoms. Differential diagnosis Morphology and immunophenotyping ((cid:9)p174) will differentiate CL L from other chronic lymphoproliferative disorders. 04-leukemia.qxd 10.12.2003 04.12 PM Page 170 Scoring system in B-cell lymphoproliferative disorders Devised to facilitate diagnosis base d on the antigen profile of CLL using a panel of 5 monoclonal antibodies1: Marker (Score) (Score) SmIg CD5 CD23 FMC7 CD79b weak positive positive negative weak (1) (1) (1) (1) (1) moderate/strong negative negative positive strong (0) (0) (0) (0) (0) 170 Total scores for CLL range from 3 \200\2235 and for non-CLL cases from 0 \200\2232. Poor prognostic factors 2 9 sex. 2 Advanced clinical stage (see below). 2 Initial lymphocyt osis > 50 109/L. 2 >5% prolymphocytes in blood movie. 2 Diffuse pattern of infiltrate on trephine. 2 Blood lymphocyte doubling time <12 months. 2 Cytogenetic abnormalities 11q \200\223 or 17q \200\223. 2 4 serum b2-microglobulin. 2 4 serum LDH. 2 4 serum thymidine ki nase. 2 4 soluble CD23. 2 Unmutated IgVH genes. 2 Poor response to therapy. \200\230Atypical CLL \200\231 includes those with >10% prolymphocytes \200\230CLL/PLL \200\231 which may show an aberrant phenotype (SmIg strong +ve, FMC7/CD79b +ve) is associat ed with trisomy 12 and p53 abnormalities and a more aggressive course. Clinical staging 2 systems widely used to classify patients as low, intermediate or high ri sk: 1 Moreau, E.J. et al. (1997) Improvement of the chronic lymphocytic leukemia scoring system with the monoclonal antibody SN8 (CD79b). Am J Clin Pathol, 108, 378 \200\223382. 04-leukemia.qxd 10.12.2003 04.12 PM Page 171 Leukemia Rai modified staging Level of risk Stage Median survival Low 0 Lymphocytosis alone >13 yrs Intermediate I II Lymphocytosis & lymphadenopathy Lymphocytosis, spleno or hepatomegaly 8 yrs 5 yrs 171 High III IV Lymphocytosis, anemia (Hb <11.0g/dL)* 2 yrs Lymphocytosis, thrombocytopenia (<100 109/L) * 1 yr not due to autoimmune anemia or thrombocytopenia. Binet clinical staging Stage Clinical features Median survival A No anemia or thrombocytopenia <3 lymphoid regions enlarged 12 yrs B No anemia or thrombocytopenia 3 or more lymphoid regions enlarged 5 yrs C Anemia (Hb \211 10g/dL) and/or thrombocytopenia ( \211 100 109/L) 2 yrs Clinical management 2 Patients with asymptomatic lymphocytosis simply require monitoring. 2 Note: some patients have very indolent disease (e.g. \200\230Smoldering CLL \200\231: Bin et stage A, non-diffuse bone marrow involvement; lymphocytes <30 109/L, Hb >12g/dL, lymp hocyte doubling time >12 months; Binet stage A with somatic mutation of IgVH gene have medi an survival 25 years). \200\223 Chemotherapy reserved for patients with symptomatic or pro gres- sive disease: anemia (Hb <10g/dL) or thrombocytopenia (<100 109/L), constitutional symptoms due to CLL (>10% weight loss in 6 months, fatigue, fever, night sweats), progress ive lymphocytosis >300 109/L; doubling time <12 months, symptomatic lym- phadenopathy/he patosplenomegaly, autoimmune disease refractory to steroids, repeated infections hypogam maglobulinaemia. \200\223 Advise patients to report infection promptly since immunocompro- mised added effects of hypogammaglobulinaemia. \200\223 Monthly IVIg reduces recurrent infections but no effect on survival. \200\223 Ma nage symptomatic autoimmune complications with corticos- teroids. 2 First line therapy generally the alkylating agent chlorambucil at a dose of 6 \200\22310m g/d (0.1 \200\2230.2mg/kg/d) PO for 7 \200\22314 days in 28 day cycles until disease stabil ized (usually 6 \200\22312 cycles). Produces improved FBC and shrinks lymph nodes and splee n in most patients. CR 3%. No effect on 04-leukemia.qxd 10.12.2003 04.12 PM Page 172 survival. Further responses in most patients if repeated on progression. Side effect myelos uppression. Long-term exposure increases risk of myelodysplasia or 2 leukemia. Cyclophosp hamide is alternative but offers no advantage. 2 Higher doses of chlorambucil (15mg/d to maximum response or toxi- city) followed by twice weekly maintenance for 3 years improves response rate and survival. \200\223 Avoid steroi ds except for autoimmune complications or for 1 \200\2232 weeks as preliminary treatment in very cytopenic patients with extensive BM infiltration. \200\223 Radiotherapy helpful for persistent or bulky lymphadenopathy; splenic irradiation is sometimes helpful in frail patients unfit for splenectomy. 172 \200\223 Splenectomy is useful therapy for massive splenomegaly or hyper- splenism. 2 Purine analog therapy induces apoptosis in CLL. Higher response rate, CR rate (27%) and p rogression-free survival but not curative. Fludarabine (25mg/m2/d IV or 40mg/m2/d PO 5 d ays q28) is cur- rently second line treatment in UK. Cladribine is an alternative. Side eff ects include infection, myelosuppression and autoimmune anemia or thrombocytopenia. 2 Note: purine analogs cause profound lymphodepletion with risk of opportunistic infection due to P carinii, M tuberculosis, H zoster and other organisms. Patients should receive cot rimoxazole prophylaxis (480mg bd tiw) throughout therapy and for 6 months post therapy and all blood products should be irradiated for 2 years post therapy. 2 Addition of cyclophosph amide (250mg/m2 IV or 400mg/m2 PO 5 days) concurrently to fludarabine improves response rates in refrac- tory patients (cid:9)p616. 2 Autologous SCT has been carried out after high dose chemotherapy TBI for younger (<55 years) patients who achieve CR with fludarabine. Remains an investigative treatment. 2 Allogeneic SCT has been successful in small numbers of younger, symptomatic patients with high risk CLL and HLA-matched siblings. 2 Campath-1H is a humaniz ed anti-CD52 monoclonal antibody (adminis- tered IV or SC) which preferentially eliminates CLL cells from blood, marrow and spleen. It has been approved in the USA for fludarabine- r efractory CLL but its role may be in the treatment of minimal residual disease after fludar abine. Side effects: immunosuppression and virus reactivation (HZV and CMV). 2 Rituximab is an anti-CD20 chimeric monoclonal antibody; less effective monotherapy than c ampath-1H; addition to fludarabine \200\223improves the de novo patient CR rate to 47% and addition to fludarabine \200\223cyclophos- phamide improves the CR rate to 66% with no evid ence of MRD by RT-PCR. Prognosis CLL remains an incurable disease with current therapy apart from a few allografte d patients but most patients with early stage, asymptomatic CLL die of other, unrelated cau ses. Infection is major cause of morbidity and mortality in symptomatic patients. Advanced stage patients eventually develop refractory disease and bone marrow failure. Terminally so me refractory patients show prolymphocytic transformation. 04-leukemia.qxd 10.12.2003 04.12 PM Page 173 Leukemia A minority (<10%) develop high grade NHL (Richter \200\231s syndrome): median interval from diagnosis 24 months; associated with all stages; abrupt onset; chemoresistant; median surv ival 4 months. Second malignancy (skin, colon) occurs in up to 20%. 173 04-leukemia.qxd 10.12.2003 04.12 PM Page 174 Cell markers in chronic lymphoproliferative disorders Mature B-cell lymphoproliferative disorders Marker CLL PLL HCL SLVL FL MCL Surface Ig weak CD5 CD10 CD11c CD19 CD20 CD22 CD23 CD25 CD79b FMC7 CD103 HC2 Cyclin D1 ++ \200\223/+ \200\223/+ \200\223 ++ + + \200\223/+ \200\223 ++ + \200\223 \200\223 + ++ \200\223 \200\223 + ++ + + \200\223 ++ + + + + \200\223/weak ++ \200\223 \200\223 +/ \200\223 ++ + + +/ \200\223 \200\223/+ ++ ++ \200\223/+ \200 \223/+ \200\223 ++ \200\223 + \200\223 ++ + +/ \200\223 \200\223/+ \200\223 ++ ++ \200\223 \200\223 \200\223 ++ + \200\223 \200\223 ++ ++ +/ \200\223 \200\223 \200\223 ++ ++ \200\223 \200\223 ++ + \200\223 \200\223/+ ++ \200\223/+ \200\223/weak ++ +/ \200\223 weak/ \200\223 \200 \223/+ \200\223 \200\223 \200\223 174 CLL, chronic lymphocytic leukemia; PLL, prolymphocytic leukemia; HCL, hairy cell leukemia; SLVL, splenic lymphoma with villous lymphocytes; FL, follicular lymphoma; MCL, mantle cell lymphoma. Mature T-cell lymphoproliferative disorders Marker T-LGLL NK-LGLL T-PLL ATLL SS TdT* CD2 CD3 CD4 CD5 CD7 CD8 CD16 CD25 CD56 Other \200\223 + ++ \200\223 + \200\223/+ ++ + \200\223 \200\223/+ \200\223 + \200\223 \200\223 + \200\223 \200\223 + \200\223 + CD11b+ CD16+ CD57+ \200\223 + ++ +/ \200\223 + +++ \200\223/+ \200\223 \200\223/+ \200\223 \200\223 + ++ ++ + \200\223 \200\223 \200\223 ++ \200\223 HTLV1+ \200\223 + ++ ++ + \200\223/+ \200\223 \200\223 \200\223 \200\223 T-LGLL, T-cell large granular lymphocyte leukemia; NK-LGLL, NK-cell large granular lym- pho cyte leukemia; T-PLL, T cell prolymphocytic leukemia; ATLL, adult T cell leukemia/lymphoma; SS, S zary syndrome. *TdT: terminal deoxynucleotidyl transferase dif- ferentiates these c ells from lymphoblasts of ALL. 04-leukemia.qxd 10.12.2003 04.12 PM Page 175 Leukemia 175 04-leukemia.qxd 10.12.2003 04.12 PM Page 176 Prolymphocytic leukemia (PLL) Uncommon aggressive clinicopathological variant of CLL with character- istic morphology and clinical features. B-cell and rare T-cell forms recog- nised. Epidemiology Median age at presentation is 67 years; 9 : 3 ratio 2:1. Accounts for <2% case s of \200\230CLL \200\231. B-PLL 75%, T-PLL 25%. Clinical features 2 Symptoms of bone marrow failure and constitutional symptoms: 176 lethargy, weight loss, fatigue, etc. 2 Massive splenomegaly, typically >10cm below costal margin may cause abdominal pain. Hepatomegaly common. 2 Minimal lymphadenopathy in B-PLL, generalized lymphadenopathy more common in T-PLL. 2 Skin lesions occur in 25% T-PLL as do serous effusions. Investigation and diagnosis 2 FBC : high WBC (typically >100 109/L; commonly >200 109 /L in T- PLL); anemia and thrombocytopenia usually present. 2 Differential shows >55% (often >90%) p rolymphocytes. 2 Morphology: large lymphoid cells, abundant cytoplasm (B-PLL mainly), prominent single central nucleolus. 2 Bone marrow diffusely infiltrated. 2 Immunophenotype: (cid:9)table p174. 2 Cytogenetics \200\224B-PLL: 14q+ in 60%; t(11;14)(q13;q32)in 20%; p53 gene abnormalities in 75%; T-PLL c hromosome 14 abnormalities in >70%; +8 in 50%. Blood movie in PLL: cells are larger than those seen in CLL but have similar \200\230matur e \200\231 nucleus. Differential diagnosis B-PLL and CLL are not always easily distinguished and mixed \200 \230CLL/PLL \200\231 recognized (>10%, <55% prolymphocytes). Clinical features, morphology and notably markers ((cid:9)p174) used to distinguish PLL from other lym- phoproliferative disorders. Management 2 PLL is typically resistant to chlorambucil. 04-leukemia.qxd 10.12.2003 04.12 PM Page 177 Leukemia 2 Splenectomy: may be symptomatically helpful, \200\230debulking \200\231, follow up with other therapy. 2 Splenic irradiation: offers symptomatic relief if unfit for splenectomy. 2 Combination ch emotherapy: CHOP may achieve responses in about 33% and prolong survival in younger patients. 2 Purine analog therapy: Fludarabine, 2-CDA or deoxycoformycin may produce responses in some patients. 177 2 Campath-1H: anti-CD52 monoclonal antibody produces responses in both B-PLL and T-PLL. In T-PLL CR rates of 40 \200\22360% have been achieved lasting severa l months and permitting subsequent high dose therapy with autologous or allogeneic SCT and prolonged survival. 2 Rituximab: anti-CD20 monoclonal antibody: there are reports of responses in B-PLL. 2 Stem cell transplantation: in view of the poor prognosis of PLL, younger patients who ach ieve a CR should be considered for allogeneic SCT where possible or autologous SCT. Natural history PLL is a relentlessly progressive disease and treatment is unsatisfactory. T- PLL carries poor prognosis with median survival 6 \200\2237 months. Median sur- vival in B-PLL is 3 years. 04-leukemia.qxd 10.12.2003 04.12 PM Page 178 Hairy cell leukemia and variant Uncommon low grade B-cell lymphoproliferative disorder associated with splenomegaly, pancyt openia and typical \200\230hairy cells \200\231 in blood and bone marrow. Epidemiology Accounts for 2% of leukaemias, 8% of chronic lymphoproliferative disor- ders. No known aetiological factors. Presents in middle age (>45 years) with 9 : 3 ratio of 4:1 Clinical features 2 Typically non-specific symptoms: lethargy, malaise, fatigue, weight los s 178 and dyspnoea. 2 15% present with infections, often atypical organisms due to mono- cytopenia. 2 30% have recurrent infection; 30% bleeding or easy bruising. 2 Splenomegaly in 80% (mass ive in 20 \200\22330%), hepatomegaly in 20%. 2 Lymphadenopathy rare (<5%). 2 Pancytopenia m ay be an incidental finding on a routine FBC. 2 Vasculitic polyarthritis and visceral invol vement similar to polyarteritis nodosa occurs in some patients with HCL. Investigation and diagnosis 2 FBC: moderate to severe pancytopenia; Hb <8.5g/dL 35%. 2 Bloo d movie: low numbers of \200\230hairy cells \200\231 in 95%; florid leukaemic fea- tures unusual 2 Hairy cells \200\224kidney shaped nuclei, clear cytoplasm and irregular cyto- plasmic projections (more notable on EM). 2 WBC differential: neutropenia, <1.0 109/L in 75%; monocytopenia is a consistent feature. 2 Cytochemistry: +ve for tartrate-resistant acid phosphatase (TRAP) in 95%; now identified by flow cytometry using antibody to TRAP. 2 Immunophenotyping: typically CD11c, CD25, CD103 & HC2 +ve; dif- ferentiates HCL from othe r chronic lymphoproliferative disorders ((cid:9)table, p174). 2 Bone marrow: aspiration often unsuccessful \200\224 \200\230dry tap \200\231 due to 4 BM fibrosis; trephine shows diagnostic features with focal or diffuse infiltra- tion of HCL wh ere cells have characteristic \200\230halo \200\231 of cytoplasm con- firmed by immunocyto chemistry with anti-CD20/DBA-44 and anti-TRAP. 2 Abdominal CT for intra-abdominal lymphadenopathy (15 \200\22320%). Differential diagnosis Confirmation of diagnosis may be difficult because of low numbers of cir- culating leukaemic cells and dry tap on marrow aspiration; trephine his- tology usual ly diagnostic; differential diagnosis includes myelofibrosis and other low grade lymphomas notably SLVL. Prognostic factors No established staging system. Response to therapy is probably the best prognostic indicator. Bulky abdominal lymphadenopathy at diagnosis cor- relates with poor r esponse to first line therapy. 04-leukemia.qxd 10.12.2003 04.12 PM Page 179 Leukemia 179 Peripheral blood movie in HCL showing typical \200\230hairy \200\231 lymphcytes. From Oxfo rd Textbook of Oncology, 2E, with permission. Management 2 In <10% patients, often elderly with minimal or no splenomegaly and cytopenia, the disease remains relatively stable and may be observed. 2 Therapy is required in patien ts with Hb <10g/dL, neutropenia <1.0 109/L, thrombocytopenia <100 109/L, symptomatic splenomegaly, recurrent infection, extralymphatic involvement, autoimmune compli- cations, florid leukemia or progressive disease. 2 Supportive management is important particularly in the early stages of therapy where cytopenias can worsen: treat infections promptly. Note: increased incidence o f atypical mycobacterial infections in HCL. 2 Splenectomy: indicated for massive splenomegaly and beneficial in man- aging severe pancy topenia in patients with minimal marrow infiltration. Non-curative but 2 \200\22315% will n ormalize FBC for up to 25 years without further therapy. Histology shows characteristic inf iltration of red pulp and atrophy of white pulp. Avoid drug therapy for 6 months after sple nectomy to assess response. 2 Purine analogs are the established first line therapy and most patients achieve a durable CR. CD4 lymphodepletion causes immunosuppres- sion: require P carinii prophylaxis and irra diated blood products. 2 Deoxycoformycin 4mg/m2 IV bolus every 1 \200\2232 weeks to maximum response plus 2 cycles (generally 6 \200\22310); check creatinine clearance pre-therapy (mu st be >60mL/min for full dose; half dose >40mL/min) improvement begins after 2 cycles; maxi mum response generally 4 \200\2237 months; 90% objective responses; 75% CR; 15% in continue d CR at 8 years; some patients are probably cured. 2 Cladribine: infusion of 0.1mg/kg/d 7 days will produce comparable remission rates; rem ission duration may be shorter; temporarily myelosuppressive, maximum 1 week after infusion ; repeat at 6 months if no CR; avoid cotrimoxazole during infusions (causes rash). 2 IFN-a 3 million units SC daily achieves a partial response in up to 80% but CR in <5%; co ntinue to maximum response then cut to three times weekly for 6 \200\22324 months or indefi nitely; normalization of blood 04-leukemia.qxd 10.12.2003 04.12 PM Page 180 counts generally occurs within 6 months and responses persist 12 \200\22315 months after di scontinuation. \200\223 IFN-a may be useful as initial therapy (tiw) for 2 \200\2234 month s before a purine analog in patients with profound cytopenias and for HCL refractory to pur ine analog therapy. Side effects cause intol- erance in some patients. 2 G-CSF may be useful in patients with severe neutropenia. 2 Monitor response by trephine b iopsy stained for CD20/DBA-44 and TRAP. Natural history Hairy cell leukemia is associated with prolonged survival (95% at 5 years), with newer agents capable of producing remissions; some patients may achieve long term cur e. For others careful application of available treat- ments at points of disease relapse/pr ogression will still allow prolonged, good quality survival. If a remission of >5 years has been achieved then a further remission with the same agent is likely. Hairy cell variant D escribes a very rare variant of HCL where the presenting WBC count is high due to circulati ng leukaemic cells (40 \200\22360 109/L) and monocy- topenia is absent. Cells are villou s but have a central round nucleus and a distinct nucleolus like PLL. Marrow is aspirated e asily due to low reticulin but the trephine appearance is similar to HCL and associated neu tropenia. Immunophenotype differs from typical HCL: CD11c+, CD25 & HC2 \200\223ve, CD103 u sually \200\223ve. Response to deoxycoformycin or IFN-a is poor but chlorambucil appears a ctive in this form, and the variant generally follows an indolent course. 180 04-leukemia.qxd 10.12.2003 04.12 PM Page 181 Leukemia 181 04-leukemia.qxd 10.12.2003 04.12 PM Page 182 Splenic lymphoma with villous lymphocytes (SLVL) Rare B-cell lymphoproliferative disorder in which marked splenomegaly and moderate lymphocy tosis represent the main clinical findings. May cor- respond histologically to splenic marg inal zone lymphoma. Clinical and laboratory features 2 Non-specific symptoms, e.g. fatigue. 2 Affects older pat ients, mean age at diagnosis 72 years. 2 Moderate to massive splenomegaly. 2 Hepatomegaly i n 50%. 2 Lymphadenopathy rare. 2 Anemia and thrombocytopenia in 25 \200\22330% usually due to hyper- 182 splenism. Neutropenia not marked. 2 Total WBC not grossly elevated (usually <40 109/L; cf. PLL). 2 Monocytopenia not a fea ture (cf. HCL) 2 Cell morphology: larger than typical CLL cells, round/oval nuclei, villous cytoplasmic projections at one/both poles of the cells. 2 Immunophenotype: CD19+, FMC7+, CD23 \200\223 usually negative for CD5 & CD25: 20% +ve but fail to co-express CD11c and CD103 differenti- ating SLVL from HCL; (cid:9)table p174. 2 Monoclonal IgM or IgG paraprotein; free urinary light chains in 66%. 2 BM aspirate may sh ow lymphocytosis (some plasmacytoid) with typical immunophenotype; biopsy may be normal but usually shows patchy/nodular lymphoid infiltratio n. 2 Spleen histology: characteristic with nodular infiltration involving the white pulp (cf. HCL). Differential diagnosis Main differentials are mantle cell lymphoma (especially 20% CD5+ SLV L) CLL, PLL, HCL and hairy cell variant. Diagnosis requires careful morpho- logical and imm unophenotypic assessment ((cid:9)p174). Prognosis and treatment Generally follows an indolent course. \211 10% may require no trea tment. Splenectomy recommended for bulky organ enlargement or hyper- splenism (and/or to co nfirm diagnosis in some cases) and can control most symptoms. Progression after splenectomy may respond to chloram- bucil or fludarabine given as for CLL. Toxic effects may be marked with purine analogs in this elderly group of patients. Median survival over 6 years. 04-leukemia.qxd 10.12.2003 04.12 PM Page 183 Leukemia 183 04-leukemia.qxd 10.12.2003 04.12 PM Page 184 Mantle cell lymphoma (MCL) B-cell derived lymphoid neoplasm defined in the WHO/REAL classifica- tion (p195) by clinica l, morphological, immunophenotypic, cytogenetic and molecular criteria. Incidence and etiology 4 \200\2238% of cases of adult NHL. Etiology unknown. t(11;14) cause s dysregu- lation of BCL-1 and overexpression of cyclin D1, a protein involved in cell prol iferation. Clinical features and presentation 2 Most common in 9 >50 years (median age 63). 2 36% have lymphocytosis in peripheral blood which may cause presen- 184 tation as ?CLL. 2 Commonly advanced disease at presentation (87%) with generalized lymphadenopathy (57%); s plenomegaly (47%); hepatomegaly (18%). 2 Extranodal involvement, particularly in GI tract is common (18%). Diagnosis and investigation 2 FBC: lymphocytosis in 36%; anemia and mild thrombocytopenia o nly in very advanced disease. 2 Blood movie: intermediate size lymphocytes; nucleus often has clefts and indentations; smear cells unusual (cf. CLL). 2 Immunophenotype: critical to diagnosis ((cid:9)p174); SmIg strongly+ CD5+, CD10 \200\223, CD19+, CD23 \200\223, CD79b+, cyclin D1+. 2 Cytogenetics: t(11;14) in 50 \200\22390% by FISH techniques. 2 Bone marrow: trephine biop sy demonstrates involvement in >70% with nodular, interstitial or diffuse patterns similar to CLL. 2 Lymph node biopsy: mantle zone expansion or diffuse effacement of nodal architecture by u niform \200\230centrocytes \200\231; characteristic immuno- chemistry pattern: CD5+, CD10 \200\223, CD79b+, cyclin-D1+. 2 Up to 30% have detectable paraprotein band, usually IgM. Differential diagnosis In patients with lymphocytosis differentiation from CLL by immunophe no- type, notably strong SmIg+, CD23 \200\223 and cyclin-D1+; from PLL when CD5+ by morphol ogy; from follicular lymphoma by CD5+, CD10 \200\223 and cyclin D1. Prognostic factors Stage using Ann Arbor system (p210). Use International Prognostic Index (p200) to assess prognosis. Age >70, HB <12g/dL, poor performance status and blood involvem ent are unfavorable features. Management and prognosis There is no evidence that MCL has been cured by either conventiona l chemotherapy or autologous SCT. Response rates of 50 \200\22390% have been achieved with COP or CHOP including CR rates of 30 \200\22350%. Median freedom from progression is <1 yea r. There is no survival advantage for anthracycline containing regimens. 2 Fludarabine \200 \223cyclophosphamide regimens ((cid:9)p616) appear to have a high response rate in previously treated patients. 04-leukemia.qxd 10.12.2003 04.12 PM Page 185 Leukemia 2 Rituximab, the anti-CD20 monoclonal antibody produces responses as a single agent and is under examination in combination with fludara- bine \200\223cyclophosphamide. 2 MCL is generally an aggressive disease with a median survival of 3 years. Most patients develop progressive refractory disease. A small number follow a more i ndolent course. 185 04-leukemia.qxd 10.12.2003 04.12 PM Page 186 Large granular lymphocyte leukemia (LGLL) Uncommon lymphoproliferative disorder, characterized by an increase in LGLs in blood. Heter ogeneous \200\224may be T-cell or NK-cell phenotype; not all cases are clonal. Clinical features 2 Any age group; median age at diagnosis 55 years. 2 Asymptomatic, modest lymphocytosis with large granular lymphocytes on routine FBC. 186 2 Occasional presentation with fatigue or recurrent bacterial infections. 2 Arthralgia, itc hing, rash (25%), mouth ulcers; association with seroposi- tive rheumatoid arthritis in 20% and Felty \200\231s syndrome (neutropenia + splenomegaly + rheumatoid arthritis). 2 Splenomegaly recorded in 50 \200\22380% cases. Lymphadenopathy rare.