h hope of improved overall survival. Chlorambucil: alkylating agent; traditional \200\230palliative \200\231 1st-line therapy; dose 6 \200\22310mg/d (0.1 \200\2230.2mg/kg/d) PO for 7 \200\22314d in 28d cycles until dis ease stabilized (usually 6 \200\22312 cycles). Improves FBC and shrinks lymph nodes and spl een in 45 \200\22386%; CR 3 \200\2237%. Median response 71 year. No eff ect on survival (75 0% at 5 years). Prior responders to chlorambucil often respond on 1 or more further occasio ns. Further responses usually poorer and shorter. Resistance inevitably develops. Only 7% r espond when fl udarabine resistant. \200 Side eff ect: myelosuppression. Prolonged use i risk of myelodysplasia or 2 leukemia. rituximab. \200 Role in treatment of older, frail patients. Remains popular in Europe. R-FC: rituximab, \202 udarabine, and cyclophosphamide: overall response (OR) 95%, with CR in 72%, nodular PR in 10%, PR due to cytopenia in 7%, and PR due to residual disease in 6% . Median follow-up of 6 years OS was 77% and PFS, 51%. The German CLL Study Group (GCLLSG) CLL8 trial showed a signifi cant improvement in response rates and duration of response wit h R-FC compared with FC alone. \200 Standard treatment for fi t and younger patients. \200 May be given in reduced doses. \200 Purine analogs cause profound lymphodepletion w ith risk of opportunistic infection due to P. jirovecii, M. tuberculosis, herpes zoster, an d other organisms. Patients should receive co-trimoxazole prophylaxis (480mg bd tiw) throug hout therapy and for 3 months post therapy and irradiated cellular blood products indefi ni tely to prevent GvHD. Alemtuzumab: achieves 39% OR rate in fl udarabine-resistant patients and appears eff ective in some refractory patients with 17p \210\222/p53 mutations. Not eff ective in bulky nodal disease (>5cm). Humanized anti-CD52 monoclonal antibody (30mg IV or SC tiw up to 18 weeks) ; preferentially eliminates CLL cells from blood, marrow, and spleen; 81% OR and 19% CR as initial therapy. \200 Side eff ects: immunosuppression and virus reactivation (HZV and CM V \200\224monitor weekly during and after treatment by CMV-PCR). Irradiate cellular blood products indefi nitely to prevent GvHD. \200 Co-trimoxazole prop hylaxis of P. jirovecii for 6 months after treatment. Recommended for use for initial therapy for CLL with 17p \210\222 and fl udarabine-refractory CLL. Bendamustine rituximab: B 70mg/m2 in cycle 1 i to 90mg/m2 if toler- ated rituximab. H igh response rates and well tolerated. Rituximab monotherapy: achieves only limited responses as a single agent in previously trea ted CLL. 164 CHAPTER 4 Leukemia Ofatumumab: also known as HuMax-CD20. Human monoclonal anti- body (for the CD20 protein) wh ich appears to inhibit early-stage B lymphocyte activation. Approved by the FDA for CLL ref ractory to fl udarabine and alemtuzumab. Approved in Europe in refractory CLL. R-CHOP: sometimes used in CLL. High-dose methylprednisolone: 1g/m2/d \227 5d every 28d; ac hieves up to 77% OR rate; median duration 9 months. May be of particular use in patients re fractory to fl udarabine with bulky disease and/or p53 muta- tions. Infection frequent. Con traindicated in patients with active peptic ulceration. Caution with diabetes and CCF. Assessment of response See Table 4.16 Table 4.16 NCI-WG response criteria for CLL4 Criteria Complete response Partial response Progressive disease Symptoms None Richter \200\231s syndrome Lymph nodes None \211 50% decrease \211 50% increase or new nodes Liver/spleen Not palpable \211 50% decrease \211 50% increase or new \211 4.0 \227 109/L \211 50% decrease \211 50% increase Lymphocytes Hemoglobin >110g/L (untransfused) >110g/L (untransfused) or 50% improvement* \211 1.5 \227 109/La >100 \227 109/La \211 1.5 \227 109/L >100 \227 109/L Neutrophils Platelets BM aspirate <30% lymphocytes BM trephine No interstitial or nodular infi ltrate May be residual lymphoid nodules a \211 1 of these features required for PR; features should be present for \211 2 months for CR or PR. Stable disease is defi ned as all other patients. 165 CHRONIC LYMPHOCYTIC leukemia (B-CLL) Stem cell transplantation Whether a SCT is indicated and at what point in a patient \200 \231s treatment remains a big challenge. As most CLL patients are elderly this does often n ot cause any concerns. The European Bone Marrow Transplant guidelines outline indications for SCT in CLL and the u se of allogeneic SCT: \200 Recommended in patients requiring treatment for CLL who have p53 abnormalities. Prognosis here is poor and they merit the risk of transplantation in 1st CR. These patients should be referred early to transplant centers. Allogeneic SCT is also recommended for some young(er) patients with CLL who fail to respond to 1st-line combination chemotherapy. Autologous SCT is not generally recommended. Treatment of complications \200 Advise patients to report infection promptly as immunocom promised. Highest risk in elderly, advanced stage, and fl udarabine treatment. Prophylactic antibioti cs or monthly IV immunoglobulin replacement therapy may reduce recurrent infections in pati ents with hypo- gammaglobulinaemia but has no eff ect on survival. Autoimmune cytopenias: manage symptomatic AIHA or ITP with corticosteroids in the 1st instance; IVIg, chemotherapy, rituximab, or splenectomy may be r equired; test patients with pure red cell aplasia for parvovirus infection; treat with pred nisolone, ciclosporin, or ATG. Radiotherapy helpful for persistent or bulky lymphadenopathy; splenic irradiation is sometimes helpful palliation in frail patients with symptomatic sple nomegaly who are unfi t for splenectomy. Splenectomy may sometimes be useful for massive splenomegaly, hypersplenism or refractory cytopenia (RR 50 \200\22388%). Lymphomatous transformation (Richter \200\231s syndrome) occurs in <10%; occurs in all stages; median interval from diagnosis 24 months; abrupt onset; progressive L N i; fever; weight loss; high LDH; usually diff use large B-cell NHL but 710% Hodgkin-like histology; chemoresistant; median survival 4 months with CHOP, better with ABVD for Hodgkin -like. Prognosis CLL remains an incurable disease with current therapy apart from a few allografte d patients. Most patients with early stage, asymptomatic CLL die of other unrelated causes. Infection is a major cause of morbidity and mortality in symptomatic patients. Advanced st age patients eventu- ally develop refractory disease and BM failure. 166 CHAPTER 4 Leukemia Cell markers in chronic lymphoproliferative disorders See Tables 4.17 and 4.18. Table 4.17 Mature B-cell lymphoproliferative disorders Marker CLL PLL HCL SMZL FL MCL Surface Ig Weak ++ ++ ++ ++ + CD5 ++ \210\222/+ \210\222 \210\222 \210\222 ++ CD10 \210\222 \210\222/+ \210\222 \210\222 + \210\222 CD11c \210\222/+ \210\222 + +/ \210\222 \210\222 \210\222 CD19 ++ ++ ++ ++ ++ ++ CD20 \210\222/+ ++ + ++ ++ ++ CD22 \210\222/weak ++ ++ ++ +/ \210\222 +/ \210\222 CD23 ++ +/ \210\222 \210\222 \210\222/+ \210\222/+ \210\222 CD25 +/ \210\222 \210\222 ++ \210\222/+ \210\222 \210\222 CD79b weak/ \210\222 ++ + ++ ++ ++ FMC7 \210\222/+ + + ++ ++ ++ CD103 \210\222 \210\222 + \210\222/+ \210\222 \210\222 HC2 \210\222 \210\222 + \210\222/+ \210\222 \210\222 Cyclin D1 \210\222 + \210\222/weak \210\222 \210\222 ++ CLL, chronic lymphocytic leukemia; PLL, prolymphocytic leukemia; HCL, hairy cell leukemia; SMZL, splenic marginal zone lymphoma; FL, follicular lymphoma; MCL, mantle cell lymphoma. 167 CHRONIC LYMPHOCYTIC leukemia (B-CLL) Table 4.18 Mature T-cell lymphoproliferative disorders Marker TdTa T-LGLL NK-LGLL T-PLL ATL SS \210\222 \210\222 \210\222 \210\222 \210\222 CD2 + + + + + CD3 ++ \210\222 ++ ++ ++ CD4 \210\222 \210\222 +/ \210\222 ++ ++ CD5 + + + + + CD7 \210\222/+ \210\222 +++ \210\222 \210\222/+ CD8 ++ \210\222 \210\222/+ \210\222 \210\222 CD16 + + \210\222 \210\222 \210\222 CD25 \210\222 \210\222 \210\222/+ ++ \210\222 CD56 \210\222/+ + \210\222 \210\222 \210\222 Other CD11b+ HTLV1+ CD57+ Genotype TCRR+ TCRR \210\222 TCRR+ TCRR+ TCRR+ T-LGLL, T-cell large granular lymphocyte leukemia; NK-LGLL, NK-cell large granular lym- pho cyte leukemia; T-PLL, T cell prolymphocytic leukemia; ATL, adult T cell leukemia/ lymphoma; SS, S zary syndrome; TCRR, clonally re-arranged T-cell receptor. aTdT: terminal deoxynucl eotidyl transferase diff erentiates these cells from lymphoblasts of ALL. References 1. Moreau, E.J. et al. (1997). Improvement of the chronic lymphocytic leukemia s coring system with the monoclonal antibody SN8 (CD79b). Am J Clin Pathol, 108, 378 \200\223 82. 2. Montserrat, E. (2006). New prognostic markers in CLL. Hematology, 2006, 279 \200\223 84. 3. Seiler, T. et al. (2006). Risk stratifi cation in chronic lymphocytic leukemia. Semi n Oncol, 33, 186 \200\22394. 4. Cheson, B.D. et al (1996). National Cancer Institute-Sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. Blood, 12 , 4990 \200\2237. Further reading Gribben, J. (2010). How I treat CLL up front. Blood, 115, 187 \200\22397. K olikaba, K.S. et al. (2013). Demographics, treatment patterns, safety, and real-world eff e ctiveness in patients aged 70 years and over with chronic lymphocytic leukemia receiving be ndamustine with or without rituximab: a retrospective study. Ther Adv Hematol, 4(3), 157 \200\22371. NCCN (2013). NCCN Guidelines on Non-Hodgkin \200\231s Lymphoma. Version I.2013. Fort Washington, PA: NCCN. M www.NCCN.org. Swerdlow, S.H. et al. (2008). WHO Classifi cati ons of Tumors of Haematopoietic and Lymphoid Tissues, 4th ed. Lyon: IARC. 168 CHAPTER 4 Leukemia Prolymphocytic leukemia (PLL) Uncommon aggressive clinicopathological variant of CLL with c harac- teristic morphology and clinical features. B-cell and rare T-cell forms recognized. Epidemiology Median age at presentation is 67 years; \231\202: \231\200 ratio 2:1. Account s for <2% cases of \200\230CLL \200\231. B-PLL 75%; T-PLL 25%. Clinical features \200 Symptoms of BM failure and constitutional symptoms \200\224letharg y, weight loss, fatigue, etc. Massive splenomegaly, typically >10cm below costal margin may cause abdominal pain. Hepatomegaly common. Minimal lymphadenopathy in B-PLL, generalized lymphadenopathy more common in T-PLL. Skin lesions occur in 25% T-PLL as do serous eff usions. Investigation and diagnosis \200 FBC: high WBC (typically >100 \227 109/L; commonly >200 \227 109/L in T-PLL); anemia and thrombocytopenia usually present. \200 Diff erential shows >55% (often >90%) prolymphocytes. \200 Morphology: large lymphoid cells, abundant cytoplasm (B-PLL mainly), prominent single central nucleolus (see Fig. 4.15). BM diff usely infi ltrated. \200 Immunophenotype: E see Table 4.17. \200 Cytogenetics \200\224B-PLL: 14q+ in 60%; t(11;14)(q13;q32)in 20%; p53 gene abnormalities in 75%; 6q \210 \222 and chromosome 1 abnormalities also described; T-PLL 14q11 abnormalities in >70%; loss of heterozygosity in 11q22 \200\22323 region aff ecting ATM gene expression in 67%; +8 in 50%. Diff erential diagnosis B-PLL and CLL are not always easily distinguished and mixed \200 \230CLL/PLL \200\231 is recognized (>10%, <55% prolymphocytes). Clinical features, mor- pho logy, and notably immunophenotyping are used to distinguish PLL from other lymphoproliferat ive disorders. 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 survival in B- PLL is 3 years. Only curative option is allogeneic SCT. 169 PROLYMPHOCYTIC leukemia (PLL) Fig. 4.15 Blood fi lm in PLL: cells are larger than those seen in CLL have large prominent nucleoli and moderate chromatin condensation (E see color plate section). Management \200 PLL is typically resistant to chlorambucil. \200 Combination chemothera py: RFC or RCHOP may achieve responses in about 33%. Purine analog therapy: fl udarabine, cladribine, or pentostatin (deoxycoformycin) may produce responses in some patients with B-PLL. Alemtuzumab: 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; may last several months and permit brid ge to allogeneic SCT in eligible patients; some prolonged survival. Rituximab: anti-CD20 monoclonal antibody produces complete responses in B-PLL that may last several months and permit subsequent SCT in eligible patients. SCT: in view of the poor prognosis of both B- and T-PLL, younger patients who achieve a CR should be considered for allogeneic SCT where possible. Splenectomy may be symptomatically helpful, \200\230debulking \200\231, but must be followed with other therapy. Splenic irradiation off ers symptomatic relief if unfi t for splenectomy. 170 CHAPTER 4 Leukemia Hairy cell leukemia and variant Uncommon low-grade B-cell lymphoproliferative disorder asso ciated with splenomegaly, pancytopenia, and typical \200\230hairy cells \200\231 in blood and BM. Epidemiology Accounts for 2% of leukaemias in adults, 8% of chronic lymphoprolifera- tive d isorders in the West. Rare in Japan. No known aetiological factors. Presents in middle age (>45 years) with \231\202: \231\200 ratio of 4:1. Clinical features \200 Typically non-specifi c symptoms: lethargy, malaise, fatigue, weig ht loss, and dyspnoea. 15% present with infections, often atypical organisms due to monocytopenia. 70% have recurrent infection; 30% bleeding or easy bruising. \200 Splenomegaly in 80% (ma ssive in 20 \200\22330%), hepatomegaly in 20%. \200 Lymphadenopathy rare (<5%). \200 Pa ncytopenia may be an incidental fi nding on a routine FBC. \200 Vasculitic polyarthritis and visceral involvement similar to polyarteritis nodosa occurs in some patients with HCL. Investigation and diagnosis \200 FBC: moderate-to-severe pancytopenia; Hb <8.5g/dL in 35% . \200 Blood fi lm: low numbers of \200\230hairy cells \200\231 in 95%; fl orid leukaemi c features unusual. Hairy cells: kidney-shaped nuclei, clear cytoplasm and irregular cytoplasmic projections (more notable on EM). WBC diff erential: neutropenia, <1.0 \227 109/L in 75%; monocytopenia is a consistent feature. Cytochemistry: +ve for tartrate-resistant acid phosphatase (TRAP) in 95%; Identifi ed by fl ow cytometry. Immunophenotyping: typically CD11c, CD25, CD103, HC2+. \200 BM: aspiration often unsucces sful \200\224 \200\231dry tap \200\231 due to i BM fi brosis; trephine shows diagnostic features with focal or diff use infi ltration of HCL where cells have a characteristic \200\230halo \200\231 of cytoplasm confi rmed by immunocytochemistry with anti-CD20/DBA-44 and anti-TRAP. Staging CT neck, chest, abdomen, pelvis recommended. Intra- abdominal lymphadenopathy in 15 \200\22320%. Diff erential diagnosis Confi rmation of diagnosis may be diffi cult because of low numbers of circulating leukaemic cells and dry tap on marrow aspiration; trephine biopsy usually d iagnostic; diff erential diagnosis includes myelofi brosis and other low grade lymphomas no tably splenic marginal zone lymphoma. Prognostic factors No established staging system. Response to therapy is probably the best prognostic indicator (see Figs. 4.16 and 4.17). 171 HAIRY CELL leukemia AND VARIANT Fig. 4.16 Peripheral blood fi lm in HCL showing typical \200\230hairy \200\231 lymphocytes (medium power) (E see color plate section). Fig. 4.17 Peripheral blood fi lm in HCL showing typical \200\230hairy \200\231 lymphocytes (high power) (E see color plate section). 172 CHAPTER 4 Leukemia Management Note: i incidence of atypical mycobacterial infections in HCL. Prophylaxis is re commended. \200 In <10% patients, often elderly with minimal or no splenomegaly and cytop enia, the disease remains relatively stable and may be observed. \200 Therapy is required in patients with Hb <10g/dL, neutropenia <1.0 \227 109/L, thrombocytopenia <100 \227 109 /L, symptomatic splenomegaly, recurrent infection, extranodal involvement, autoimmune compl ications, fl orid leukemia, or progressive disease. Supportive management is important particularly in the early stages of therapy where cytope nias can worsen: treat infections promptly. 1st-line therapy Cladribine: purine analog; widely used as 1st-line therapy. 0.14 mg/kg SC injection once daily d1 \200\2235. 80% CR rate, remainder PR; temporary myelosuppression. R epeat at 6 months if no CR; 54% progression-free survival at 12 years; some patients likely cured. Pentostatin (deoxycoformycin): alternative purine analog; 4 mg/m2 IV bolus every 2 weeks to maximum response plus 2 cycles (generally 6 \200\22310); improvement expected afte r 2 cycles; maximum response gener- ally 4 \200\2237 months; up to 90% OR; 75% CR; 15% cont inued CR at 8 years; some patients likely cured. G-CSF: may be useful in patients with severe neutropenia. Splenectomy: now rarely required; reserved for patients unresponsive to therapy. Avoid drug therapy for 6 months after splenectomy to assess response. After purine analog therapy CD4 lymphodepletion causes immuno- suppression: requires P. jir ovecii prophylaxis with co-trimoxazole for 6 months after treatment and irradiated blood pr oducts indefi nitely. Monitor response to therapy at 3 months by trephine biopsy. 2nd-line and subsequent therapy Immediate retreatment is not always necessary when relapse is identi- fi ed. If a remission of >5 years has been achieved then a further remis- sion w ith the same agent is likely. The second remission is likely to be shorter. Early relapse o r resistance may benefi t from an alternative purine analog, interferon alfa, or rituximab. Interferon alfa: 3 million units SC 3 \227/week continued for 12 \200\22318 months may be u seful for HCL refractory to purine analogs; initial therapy achieves PR in up to 80% but CR in <5%; lower responses later in disease; Side eff ects notably fl u-like symptoms and fat igue cause intoler- ance in some patients. Rituximab: 375mg/m2/week IV \227 4 \200\22312; off ers an alternative to patients resistant to purine analogs. 26 \200\22380% ORs and 10 \200\22355% CRs have been reported with median responses of 14 \200\22373 months. 173 HAIRY CELL leukemia AND VARIANT Natural history Hairy cell leukemia treated with a purine analog is associated with prolong ed survival (95% at 5 years, 80 \200\22387% at 10 \200\22312 years), with many patients ach ieving durable CRs; some patients may be cured. For others, careful application of availabl e treatments at disease relapse or progres- sion allows prolonged, good quality survival. L ate relapses occur. Hairy cell variant Describes a rare variant of HCL where the presenting WBC count is higher due to circulating leukaemic cells (40 \200\22360 \227 109/L) and mono- cytopenia is abse nt. Cells are villous but have a central round nucleus and a distinct nucleolus-like PLL. M arrow is aspirated easily due to low reticulin but the trephine appearance is similar to HC L. There is often an associated neutropenia. Immunophenotype diff ers from typical HCL: CD1 1c+, CD25, and HC2 \210\222ve, CD103 usually \210\222ve. Response to pen- tostatin (deoxy coformycin) or interferon alfa is poor but chlorambucil appears active in this form, and th e variant generally follows an indolent course. Further reading Chadha, P. et al. (2005.) Treatment of hairy cell leukemia with 2-chlorodeo xyadenosine (2-CdA): long term follow-up of the Northwestern University experience. Blood, 106, 241 \200\2236. Jones, G. et al. (2012). Revised guidelines for the diagnosis and manag ement of hairy cell leukemia and hairy cell leukemia variant. Br J Haematol, 156(2), 186 \200\22395. 174 CHAPTER 4 Leukemia Large granular lymphocyte leukemia (LGLL) Uncommon clonal lymphoproliferative disorders, ch aracterized by an increase in LGLs in blood. Heterogeneous \200\224may be either T-cell or NK-cell phenotype; each may follow an indolent or aggressive course. T-cell LGLL Most frequent form of LGLL, 85% of LGL patients. Etiology unclear. Clinical features \200 Median age at diagnosis 60 years; no gender preference. \200 Usu ally asymptomatic; modest lymphocytosis on routine FBC with large granular lymphocytes >2 \227 109/L (NR 0.2 \200\2230.4 \227 109/L) (see Fig. 4.18). 80% develop neutropenia; >45% <0.5 \227 109/L. \200 Occasional presentation with chronic fatigue or recurrent bacterial infections \200\224usually mucocutaneous. Arthralgia, itching, rash (25%), mouth ulcers; association with seropositive rheumatoid arthritis in 25 \200\22335% and Felty syndrome (neutropenia + splen omegaly + rheumatoid arthritis). \200 Splenomegaly 20 \200\22350% of cases. Lymphadenopat hy rare. Laboratory \201 ndings \200 Hb and platelets usually normal; chronic neutropenia (80%) and mild anemia (48%) may be present. Thrombocytopenia 20%. Mild/moderate lymphocytosis (usually <10 \227 109/L); medium-large cells; eccentric nucleu s; abundant cytoplasm and distinct azurophilic granules. Phenotyping: most type as \200\230cytotoxic \200\231 T cells (CD3+ CD8+ CD16+ CD56 \200 \223 CD57+); variants co-express CD4 and CD8, CD4 alone or neither; weak expression of CD5 and CD7 distinguishes from reactive LGLs. Clonal rearrangement of T-cell receptor genes (TCR & ) confi rms diagnosis by RFLP and Southern blotting (TCR ) and PCR (TCR ). Polyclonal hypergammaglobulinaemia, rheumatoid factor, and antinuclear antibodies occur in 50% even without joint disease. BM involvement often subtle; may be diff use or nodular usually non- paratrabecular; anti-CD3 immunohistochemistry helps. \200 No characteristic cytogenetic p attern; <10% abnormal. Diff erential diagnosis Reactive lymphocytosis (screen for infection especially EBV); other T-cell lymphoproliferative disorders (immunophenotype; E see Table 4.16, p.164). 175 LARGE GRANULAR LYMPHOCYTE leukemia (LGLL) Prognosis and management \200 Incurable but generally stable benign disease. Asymptomatic patients require observation only. Care is essentially supportive with prompt treatment of infection with appropriate broad-spectrum antibiotics. Treatment indicated by development of recurrent infections, severe neutropenia, symptomatic anemia or thrombocytopenia or symptomatic splenomegaly or s ystemic symptoms. Immunosuppression with low-dose methotrexate (10mg/m2 PO weekly), ciclosporin (2mg/kg PO bd) or cyclophosphamide (50 \200\223100mg PO od) eff ect ive in >50% of patients. Treat for at least 4 months to assess response; indefi nite treatm ent may be necessary to sustain response. Symptoms may improve without improved neutrophil count; failure to eradicate clone does not prevent improvement in cytopenias. \200 Corticosteroids in modest dosage may improve neu tropenia but predispose to infection, including fungal infections; responses less durable. Prophylactic antibiotics can be helpful in severe neutropenia on steroid therapy. G-CSF may be of value in symptomatic chronic neutropenia. \200 Alemtuzumab and purine ana log drugs are reported to be eff ective as single agents in refractory T-LGLL. Aggressive T-cell LGLL Rare; aff ects younger age-group: median age 41 years, range 9 \200 \22364. Present with rapidly progressive B symptoms (fever, nightsweats, weight loss), hepatospleno megaly, lymphadenopathy, lymphocytosis, anemia, and/or thrombocytopenia. \200 Poor progno sis; survival 2 months \200\2232 years. \200 Diagnosis by aggressive course plus FBC: LGL s >0.5 \227 109/L, many >10 \227 109/L. Immunophenotype: CD3+, CD8+, CD56+, TCR , or variants; clonally rearranged TCR and genes. Diff erentiate from: indolent T-cell LGLL: indolent clinical course, neutropenia, autoimmune disease, and CD56 \200\223. Aggressive NK-LGLL: sCD3 \200\223, germ line TCR genes, intracellular clonal episomal EBV; usually Asian patient. Optimal therapy undefi ned; treat with ALL-type regimen including CNS prophylaxis followed by SCT in 1st CR. 176 CHAPTER 4 Leukemia Fig. 4.18 Blood fi lm showing large granular lymphocytes in LGL leukemia. Chronic NK-cell LGLL \200 5% of LGL patients; median age 58. \200 Etiology unclear. Pos sible role of viral infection. Clinical and laboratory features \200 Indolent disorder with favorable prognosis. \200 Persistently elevated LGLs (>2 \227 109/L). \200 No fever, hepatosplenomegaly, or lympha denopathy. \200 Mild neutropenia and/or anemia may occur; less severe and less frequent than in indolent T-cell LGLL. Immunophenotype: typically CD2+, CD3 \210\222, CD8 \210\222, CD16+, CD56+, CD57 variable. Demonstration of clonality and diff erential diagnosis from reactive NK-cell lymphocytosis can be diffi cult; panels vs NK-associated antigens can be helpful; reactive lymphocytosis associated with viral infection and connective tissue disorders and rarely last >6 months; diff erentiate from indolent T-cell LGLL by immunophenotype and TCR clonal studies. Treatment As for indolent T-cell LGLL. Aggressive NK-cell LGLL 10% of LGL patients; most prevalent in younger Asian patients. Medi an age 39 years; no gender preference. Association with EBV infection (?aetiological role). Clinical and laboratory features \200 Acute presentation with B symptoms, hepatosplenomeg aly, and cytopenia. DIC and multiorgan failure may occur. BM: diff use infi ltration by NK cells. \200 Diagnosis by immunophenotype CD2+, CD3 \210 \222, CD56+, usually CD57 \210\222; germline TCR genes; clonal episomal EBV. Cytogenetics: del(6q21-q25) and \210\22217p13 most common. 177 LARGE GRANULAR LYMPHOCYTE leukemia (LGLL) Treatment CHOP-type therapy ineff ective. Consider ALL-type regimen with CNS prophylaxis as initial therapy; consolidate responders with SCT. Further reading Alekshun, T.J. and Sokol, L. (2007). Diseases of large granular lymphocytes . Cancer Control, 14, 141 \200\22350. 178 CHAPTER 4 Leukemia Adult T-cell leukemia-lymphoma (ATLL) Aggressive neoplasm of CD4-+ve T-lymphocytes caused b y HTLV-I with a distinct geographical distribution. Incidence Highest incidence among populations where HTLV-I infection endemic: Kyushi distri ct of SW Japan, Caribbean, parts of Central and South America, Central and West Africa. Inc idence 2/1000 \231\202 and 0.5 \200\2231/1000 \231\200 seropositive for HTLV-I (37% \231 \202 >40). HTLV-1 infection: ATLL risk 2.5% at 70 years. Non-endemic cases generally origin ate from these areas. Etiology HTLV-I involved in multistep pathogenesis. HTLV-I provirus in ATLL cells; all pati ents with ATLL are seropositive for prior HTLV-I infection. Transfer of live infected cells required for infection; 3 major routes: mother to infant (mainly by breast milk); parenter al transmission; sexual transmission. Not all infected patients develop ATLL. Often long la tent period (40 \200\22360 years). Clinical subtypes There are 4 subtypes: acute, chronic, smoldering, and lymphomatous forms. Acute subtype most common (66%), median survival 6 months despite therapy. Other forms hav e longer survival but often progress to the acute form after several months. Median surviva l of lymphomatous subtype 1 year and chronic subtype 2 years. The smoldering subtype is mos t indolent and is associated with survival >24 months. Clinical features and presentation \200 Median age at diagnosis 58 years (range 20 \200 \22390); \231\202: \231\200 ratio 1:4. \200 History of residence or origin in HTLV-I end emic area usual. \200 Usually short history of rapidly increasing ill health. \200 Oppo rtunistic infection common. \200 Acute subtype: abdominal pain, diarrhea, pleural eff usi on, ascites, and respiratory symptoms (often due to leukaemic infi ltration of lungs). Lymp hadenopathy 60%; hepatomegaly 26%, splenomegaly 22%; skin lesions 39%. Lymphomatous subtype: prominent lymphadenopathy; few circulating cells. Chronic subtype: mild i WBC; some skin lesions, enlarged LN, organomegaly. Smoldering subtype: few ATLL cells, skin lesions, and occasional pulmonary involvement. 179 ADULT T-CELL leukemia-LYMPHOMA (ATLL) Diagnosis and investigation \200 FBC: WBC usually markedly i (up to 500 \227 109/L) in a cute form but may be normal; anemia and thrombocytopenia common. Blood fi lm: large numbers of lymphoid cells with marked nuclear irregularity occasionally multilobulated with \200\230fl oral \200\231 or \200\230clover leaf \200\231 appearance (Fig. 4.19). Immunophenotyping: generally CD2+, CD3+, CD4+, CD5+, CD7 \210\222, CD8 \210\222, CD25+, HLA -DR+ T cells; rarely CD4 \210\222, CD8+ or CD4+, CD8+ (E see Table 4.18). Serology: +ve for HTLV-I. \200 Cytogenetics: multiple abnormalities described; no consist ent pattern. \200 Serum chemistry: hypercalcaemia in 33 \200\22350% of patients at diagno sis; 70% during disease course due to i osteoclasts. BM: diff use infi ltration by ATL cells. \200 Monoclonal integration of HTLV-I provirus i n lymphoid cells can be demonstrated by Southern blotting. (a) (b) Fig. 4.19 Peripheral blood fi lms showing typical ATL cell with lobulated \200\230clover l eaf nucleus \200\231 (E see color plate section). Prognostic factors Poor prognostic features: \200 Raised LDH. \200 Hypercalcaemia. \200 Hyperbilirubinaemia. \200 Raised WBC. 180 CHAPTER 4 Leukemia Management and prognosis \200 Treatment unsatisfactory; poor prognosis in acute and lymph omatous ATLL: median survivals 6 and 10 months respectively. Death is usually due to opport unistic infection. Patients with acute and lymphomatous ATLL require immediate treatment; patients with chroni c or smoldering ATLL may be observed. The combination of AZT and IFN is highly eff ective and is standard 1st-line therapy in acu te leukaemic ATLL, as well as smoldering and chronic ATLL. This combination has changed the natural history of the disease in patients with smoldering and chronic ATLL as well as a s ubset of patients with acute ATLL. \200 Use in leukaemic forms of the disease as 1st-line therapy and not after 1 or more cycles of chemotherapy. Start with high doses of both agents. Lymphomatous ATLL: CHOP in addition to or followed by antiretroviral therapy with AZT/IFN. CHOP (with G-CSF) achieves 66% OR with 25% CR; median survival <1 year; OS at 3 years is 13%. \200 Prophylaxis of opportunistic infections and supportive therapy should be given. Allogeneic SCT should be considered in suitable patients in 1st CR. \200 GvL eff ect appe ars important. Reduced-intensity conditioning safer in older patients (most >50 years). Donors should be HTLV-I seronegative as donor cel l transformation to ATL reported. Further reading Bazarbachi, A. et al. (2011). How I treat adult T-cell leukemia/lymphoma. B lood, 118, 1736 \200\22345. Yasunaga, J. and Matsuoka, M. (2007). Human T-cell leukemia vir us type 1 induces adult T-cell leukemia: from clinical aspects to molecular mechanisms. Can cer Control, 14, 133 \200\22340. 181 Chapter 5 Lymphoma Non-Hodgkin lymphoma (NHL) 182 International Prognostic Index 187 Indolent lymphoma 190 Tre atment of indolent lymphoma 194 Aggressive lymphomas 198 Initial treatment of aggressive ly mphomas 204 Salvage therapy in aggressive lymphomas 208 Response criteria for lymphoma 209 Role of FDG-PET scanning in NHL diagnosis and treatment 210 CNS lymphoma 212 Hodgkin lympho ma (HL) 214 Treatment of HL 220 182 CHAPTER 5 Lymphoma Non-Hodgkin lymphoma (NHL) NHL is a group of histologically and biologically heterogeneous clonal malignant diseases arising from the lymphoid system. The clinical presen- tation ran ges from an indolent to an aggressive nature. Treatment deci- sions are preferably made in a multidisciplinary setting. Epidemiology Lymphoma (both NHL and HL) is the most common hematological cancer (5% of all cancer cases). The annual incidence of \200\230lymphoma \200\231 in Western countries is 1 5 \200\22320 cases per 100,000. Incidence i with age. \231\202: \231\200 ratio 3:2. The la st decades have seen an increase; i incidence is in part due to i mean age of the populatio n, improvements in diagnosis, the HIV pan- demic, and immunosuppressive therapy and diagnos is (including HIV). Etiology The rearrangement and mutation of immunoglobulin genes that occur in B-cell diff e rentiation and the response to antigen off ers an opportu- nity for genetic accidents such as translocations or mutations involving immunoglobulin gene loci that have been characteri zed in many lym- phomas. Most translocations involve genes associated with either prolif- e ration (e.g. c-MYC) or apoptosis (e.g. BCL-2). Other factors associated with NHL are: \200 Congenital immunodefi ciency: ataxia telangie ctasia, Wiskott \200\223Aldrich syndrome, X-linked combined immunodefi ciency. Acquired immunodefi ciency: immunosuppressive drugs, transplantation, HIV infection. Infection: HTLV-I (ATLL); EBV (Burkitt lymphoma, HL); Helicobacter pylori (gastric mucosa-associated lymphoid tissue (MALT) lymphomas). Environmental toxins: agricultural pesticides, herbicides, and fertilizers, solvents and hair dyes. Familial: risk i 2 \200\2233-fold in close relatives (?environmental). Classi \201 cation The World Health Organization (WHO) classifi cation of lymphoid neoplas ms superseded the previous Revised European American Lymphoma (REAL) classifi cation. The m ost recent 2008 WHO classi- fi cation (E Table 5.1) lists over 80 diff erent clinical-patho logical lym- phomas using morphology, immunophenotype, genotype, cell of origin, and clinic al behavior. 85% of lymphomas are B-cell type, the remaining lymphomas are of T/NK-cell ori gin. The extensive list includes all entities and also includes provisional enti- ties for which the WHO Working Group felt there was insuffi cient evi- dence to recognize as distinct dis eases at this time. The most common and least rare lymphomas are discussed in this chapter. Clinical behavior of lymphomas most often determines management strategies in clinical prac tice; treatment protocols remain largely based on classifi cation systems that group diagno ses into indolent (low-grade) and aggressive (high-grade) NHL. 183 NON-HODGKIN LYMPHOMA (NHL) The more biologically relevant classifi cation of lymphoma diagnosis using the WHO classifi cation, together with emerging therapeutic options based on immunological and molecular ch aracteristics will increase the diagnosis-specifi c nature of therapy in the future. Table 5.1 WHO classifi cation of lymphoid neoplasms1,2 Mature B-cell neoplasms Chronic lymphocytic leukemia/small lymphocytic lymphoma B-cell prolymphocytic leukemia Sple nic B-cell marginal zone lymphoma Hairy cell leukemia Splenic B-cell lymphoma/leukemia, unc lassifi able Splenic diff use red pulp small B-cell lymphoma Hairy cell leukemia-variant Ly mphoplasmacytic lymphoma Waldenstr m macroglobulinaemia Heavy chain diseases Alpha heavy c hain disease Gamma heavy chain disease Mu heavy chain disease Plasma cell myeloma Solitary plasmacytoma of bone Extraosseous plasmacytoma Extranodal marginal zone lymphoma of mucosa- associated lymphoid tissue (MALT lymphoma) Nodal marginal zone lymphoma Pediatric nodal mar ginal zone lymphoma Follicular lymphoma Pediatric follicular lymphoma Primary cutaneous fol licle center lymphoma Mantle cell lymphoma Diff use large B-cell lymphoma (DLBCL), NOS T-ce ll/histiocyte rich large B-cell lymphoma Primary DLBCL of the CNS Primary cutaneous DLBCL, leg type EBV-positive DLBCL of elderly DLBCL associated with chronic infl ammation Lymphoma toid granulomatosis Primary mediastinal (thymic) large B-cell lymphoma Intravascular large B-cell lymphoma ALK positive large B-cell lymphoma Plasmablastic lymphoma Large B-cell lymp homa arising in HHV8-associated multicentric Castleman disease Primary eff usion lymphoma B urkitt lymphoma B-cell lymphoma, unclassifi able, with features intermediate between diff u se large B-cell lymphoma and Burkitt lymphoma B-cell lymphoma, unclassifi able, with featur es intermediate between diff use large B-cell lymphoma and classical Hodgkin lymphoma (Continued) 184 CHAPTER 5 Lymphoma Table 5.1 WHO classifi cation of lymphoid neoplasms1,2 (Continued) Mature T-cell and NK-cel l neoplasms T-cell prolymphocytic leukemia T-cell large granular lymphocytic leukemia Chronic lymphopro liferative disorder of NK-cells Aggressive NK cell leukemia Systemic EBV positive T-cell ly mphoproliferative disease of childhood Hydroa vacciniforme-like lymphoma Adult T-cell leuke mia/lymphoma Extranodal NG/T cell lymphoma, nasal type Enteropathy-associated T-cell lympho ma Hepatosplenic T-cell lymphoma Subcutaneous panniculitis-like T-cell lymphoma Mycosis fun goides S zary syndrome Primary cutaneous CD30-positive T-cell lymphoproliferative disorder s Lymphomatoid papulosis Primary cutaneous anaplastic large cell lymphoma Primary cutaneous gamma-delta T-cell lymphoma Primary cutaneous CD8 positive aggressive epidermotropic cytot oxic T-cell lymphoma Primary cutaneous CD4 positive small/medium T-cell lymphoma Peripheral T-cell lymphoma, NOS Angioimmunoblastic T-cell lymphoma Anaplastic large cell lymphoma, AL K positive Anaplastic large cell lymphoma, ALK negative Hodgkin lymphoma Nodular lymphocyte predominant Hodgkin lymphoma Classical Hodgkin lymphoma: Nodular scleros is Hodgkin lymphoma Lymphocyte-rich classical Hodgkin lymphoma Mixed cellularity Hodgkin ly mphoma Lymphocyte depleted Hodgkin lymphoma The italicized histological types are provisional entities, for which the WHO Working Group felt there was insuffi cient evidence to recognize as distinct diseases at this time. 185 NON-HODGKIN LYMPHOMA (NHL) Presentation The features at presentation refl ect a spectrum from \200\230low-grade \200 \231 lym- phoma (typically, widely disseminated at diagnosis but with indolent course) to \200\230high-grade \200\231 lymphoma (short history of localized rapidly enlarging lymphade nopathy constitutional symptoms ( \200\230B-symptoms \200\231: drenching night sweats, > 10% weight loss and/or fevers). Almost 75% of adults present with nodal disease, usually superfi cial pain- less lymphadeno pathy. 25% are extranodal (750% in the Far East) and may present with oropharyngeal involve ment (5 \200\22310%), GI involvement (15%), CNS involvement (5 \200\22310%), skin involveme nt (mainly T-cell lym- phomas). Patients with GI involvement have a higher frequency of oropharyngeal involvement (Waldeyer \200\231s ring) and vise versa. Hepatosplenomegaly is common in advanced disease. Diagnostic and staging investigations \200 Histological diagnosis by expert haematopathol ogist: excision biopsy of lymph node or extranodal mass with immunohistochemistry molecu lar analysis. NB Fine needle aspirate (FNA) is inadequate for reliable diagnosis and grading. Detailed history including B symptoms. \200 Physical examination and performance status. \200 FBC and blood fi lm. \200 LDH. \200 CRP/ESR. \200 Serum 2-microglobulin. \200 U&E, uric acid, LFTs. \200 DAT screen. \200 Serum protein electrophoresis. \200 Plasma viscosity can be considered. \200 BM aspirate and trephine biopsy. \200 CXR. \200 Imaging: whole-body CT neck, chest, abdomen, and pelvis or PET/ CT scan; CT or MRI he ad/spine for patients with CNS symptoms; other imaging as indicated. LP also for high-grade disease with BM, testicular, paranasal sinus,