21. Campbell, P.J. and Green, A.R. (2005). Management of polycythemia vera and essential thrombocythemia. Hematology, 2005, 201 \200\2238. 22. Landolfi , R. and Di Gennaro, L. (2008). Prevention of thrombosis in polycythemia vera and essential thrombocythemia. Haematologica, 93, 331 \200\2235. 23. McCarthy, L. et al. (2002). Erythromelalgia due to essential thrombocthemia. Transfusio n, 42, 1245. 24. Cortelazzo, S. et al. (1995). Hydroxyurea for patients with essential thrombocythemia a nd a high risk of thrombosis. N Engl J Med, 332, 1132 \200\2236. 25. Harrison, C.N. et al. (2005). Hydroxyurea compared with anagrelide in high-risk essenti al thrombocythemia. N Engl J Med, 353, 33 \200\22345. 26. Finazzi, G. et al. (2005). Acute leukemia in polycythaemia vera: an analysis of 1638 pa tients enrolled in a prospective observational study. Blood, 105, 2664 \200\22370. 27. Barosi, G. et al. (2007). A unifi ed defi nition of clinical resistance/intolerance to hydroxyurea in essential thrombocythemia: results of a consensus process by an internationa l working group. Leukemia, 21, 277 \200\22380 plus corrigenda 21, 1135. 28. Barbui, T. and Finazzi, G. (2006). Myeloproliferative disease in pregnancy and other management issues. Hematology, 2006, 246 \200\22352. 29. Passamonti, F. et al. (2007). Increased risk of pregnancy complications in patients wit h essential thrombocythemia carrying the JAK2 (617V>F) mutation. Blood, 110, 485 \200\2239. 30. Harrison, C. (2005). Pregnancy and its management in the Philadelphia-negative myeloproliferative diseases. Br J Haematol, 129, 293 \200\223306. 31. Beer, P. et al. (2011). How I treat essential thrombocythemia. Blood, 117, 1472 \200 \22382. Further reading Swerdlow, S.H. et al. (2008). WHO Classifi cations of Tumors of Haematopoie tic and Lymphoid Tissues, 4th ed. Lyon: IARC. 290 CHAPTER 7 Myeloproliferative neoplasms Reactive thrombocytosis Platelet counts of >450 \227 109/L occur as a reactive phenomenon and maybe seen in: \200 Infection. \200 Following surgery. \200 Post splenectomy or f unctional asplenia. \200 Malignancy, e.g. occult carcinoma. \200 Trauma. \200 Chronic infl ammatory states, e.g. collagen disorders. \200 Blood loss. \200 Fe defi ciency. \200 Haemolytic anemia. \200 Rebound in response to haematinics and/or chemotherapy. \200 Any severely ill patient on ITU. Raised platelet count in clonal hematological disorders occurs in CML, ET, PV, PMF, and als o in MDS (esp. 5q \210\222 syndrome). In RT platelets are usually <1000 \227 109/L but lev els of 1500 \227 109/L may occur. Platelet morphology usually normal but diff erentiation from ET relies on full clinical evaluation. BM examination if done reveals i megakaryocytes with n morphology. RT is generally not associated with an i risk of thrombosis or haemor- rhage and no specifi c treatment is required. However, short-term anti- coagulant or antiplatelet therapy is ad vised for marked thrombocytosis occurring in the immediate post-splenectomy period as an i incidence of thrombosis has been described in this situation. Improvement or resolution of the underlying cause usually results in normalization of the p latelet count in RT. 291 REACTIVE THROMBOCYTOSIS 292 CHAPTER 7 Myeloproliferative neoplasms Primary myelo \201 brosis 1 myelofi brosis (syns. idiopathic myelofi brosis (IMF), myelofi brosis with myeloid meta plasia) is a MPN characterized by marrow fi brosis, splenomegaly, extramedullary haematopoi esis, and teardrop poikilo- cytes and leucoerythroblastosis in the peripheral blood fi lm. Cases of myelofi brosis (MF) that evolve from PV (10 \200\22315% evolve into MF) or ET (72% evolve to MF) are designated post-PV myelofi brosis and post-ET myelofi brosis respectivel y. The term PMF is reserved for de novo cases. Incidence Rare disorder; 75 cases per million per annum; predominantly elderly patients (me dian 65 years); aff ects \231\202 and \231\200 equally. Pathogenesis \200 PMF is a clonal neoplastic proliferation arising from an early haematopoietic stem cell that leads to marked hyperplasia of morphologically abnormal megak aryocytes and clonal monocytes that stimulate reactive fi brosis of the BM. The JAK2-V617F mutation has been found in up to 58% of patients with PMF;1 it is homozygous in 13% of patients with PMF compared to 30% with PV and rare in ET.2,3 Presence of JAK2-V617F may correlate with poorer survival in PMF;4 homozygosity is associat ed with more frequent unfavorable cytogenetic abnormalities.5 The MPL-W515L or MPL-W515K mutation of the transmembrane domain of the thrombopoietin recep tor (cMPL) has been detected in 9% of patients with JAK2-V617F \210\222ve PMF; these mutat ions can co-exist in the same patient; 30% of patients with a cMPL mutation also have the J AK2-V617F mutation;6 the burden of each mutation appears to remain constant over time.7 Patients with MPL-W515L/K mutations may be older, have more severe anemia, and be more likely to require transfusion support.8 750% of patients with clinically similar PMF have no detectable mutation of JAK2 or cMPL, so these mutations cannot be the only cause of PMF and other gene tic events clearly contribute to the development of PMF; gains of genetic material occur in >50% of patients, most commonly 9p, 2q, 3p, 4, 12q, and 13q.9 PMF fi broblasts are non-clonal; fi brosis is a reactive process in response to cytokines r eleased by clonal megakaryocytes and monocytes, notably TGF- ,10 PDGF, IL-1, EGF, calmodul in, and bFGF may also play a role. Exaggeration of normal BM reticulin pattern progresses to intense collagen fi brosis that d isrupts and fi nally obliterates normal marrow architecture; ultimately osteosclerosis may develop. High levels of endothelial progenitors appear in PB in the prefi brotic phase and haematopoietic progenitors (CD34 cells) increase as PMF advances which facilitate s seeding of extramedullary haematopoiesis.11 293 PRIMARY MYELOFIBROSIS Extramedullary haematopoiesis develops in spleen and/or liver, and occasionally other sites , e.g. lymph nodes, skin, and serosal surfaces. Marrow fi brosis can also occur 2 to other disorders: a minority may follow chemotherapy or radiotherapy; can develop in response to chronic myeloproliferat ive disorders, myelodysplasia, and 2 to carcinomatous involvement. Clinical features and presentation \200 720% may be asymptomatic at diagnosis: mild abnor malities identifi ed on routine FBC or splenomegaly on clinical examination. 70 \200\22380% are diagnosed in the fi brotic stage; most present with symptoms of progress ive anemia and hepatosplenomegaly associated with hypercatabolic features of fatigue, weigh t loss, night sweats, and low-grade fever. Abdominal discomfort (heavy sensation in left upper quadrant), early satiety and/or dyspeps ia from pressure eff ects of splenic enlargement may prompt presentation. Symptoms and signs of marrow failure: lethargy, infections, bleeding. \200 Splenomegaly i s almost universal (>90%): moderate-to-massive (35%) enlargement; variable hepatomegaly (up to 70%); lymphadenopathy is uncommon (<10%). Gout in 75%; portal hypertension, pleural eff usion, and ascites (due to portal hypertension or peritoneal seeding) also occur. 20 \200\22330% of patients with PMF are diagnosed in pre-fi brotic stage which may clinical ly mimic ET; it evolves from hyperproliferation of megakaryocytes with moderate-to-marked t hrombocytosis (88% \211 500 \227 109/L), occasionally with thrombosis or bleeding, mild anemia, mild-to-moderate leucocytosis, and no or modest splenomegaly (15%) to classical fi brotic PMF.12 Investigations and diagnosis \200 FBC: Hb usually d or n (<10g/dL in 60%); normochromic n ormocytic indices; WBC may be d, n or i (730%; rarely >100 \227 109/L); basophilia and eosinophilia in 10 \200\22330%; platelets usually d or n; occasionally i. Blood fi lm: Prefi brotic stage: thrombocytosis and mild leucocytosis but no or minimal red cell poikilo cytosis, teardrops, or leucoerythroblastosis. Fibrotic stage: leucoerythroblastic anemia (nucleated red cells, myelocytes) with teardrop poikilocytes (96%) and polychromasia; giant platelets and megakar yocyte fragments. BM aspirate: usually unsuccessful ( \200\230dry tap \200\231). \200 BM trephine biopsy: e ssential for diagnosis: Characteristically shows patchy haemopoietic cellularity (often focally hypercellular); i n umbers of small-to-large irregular megakaryocytes with aberrant nuclear \200\223cytoplasmic ratio and hyperchromatic, bulbous, or irregularly folded nuclei and dense clustering; bare megakaryocyte nuclei common; usually reticulin fi brosis (often coarse and branching) and/ or collagen fi brosis; distended marrow sinusoids with intravascular haematopoiesis (Fig. 7 .1). 294 CHAPTER 7 Myeloproliferative neoplasms Prefi brotic stage: minimal or absent reticulin fi brosis, i cellularity due to granulocyte proliferation and often d erythropoiesis; diff erentiate from ET by i atypical megakaryocy tes. JAK2 mutation analysis: +ve in 58%. \200 Coagulation screen: features of (chronic) DIC in 15%; usually occult but causes problems at surgery (e.g. splenectomy); defective platelet aggregation common. Cytogenetics: abnormalities in up to 50%: 13q \210\222, 20q \210\222, +8, +9, t(1;7), der(6), t(1;6),(q21723;p21.3), 12p \210\222, 7 \210\222, 7q \210\222, and 1q+ most frequent; exclude Ph chromosome by FISH on PB if dry tap on BM. \200 Serum chemistry: bil irubin i in 40%; alkaline phosphatase and ALT i in 50%; urate i in 60%. LDH i due to ineff ective erythropoiesis and haemolysis; i in 20% of prefi brotic MF. Serum ferritin: to assess Fe stores; d by occult GI blood loss in subclinical PV. Serum EPO: patients with level <125U/L respond more readily to EPO therapy. Vitamin B12 often raised. \200 Skeletal radiology: to assess osteomyelosclerosis. \200 MRI: readily distinguishes fi brotic BM from cellular BM. Fig. 7.1 BM trephine in myelofi brosis: note streaming eff ect caused by intense fi brosis (E see color plate section). 295 PRIMARY MYELOFIBROSIS Diff erential diagnosis \200 Exclude other myeloproliferative neoplasms (CML, PV, ET), AM L M7 ( \200\230acute MF \200\231), myelodysplasia, lymphoproliferative disorders (particula rly HCL), metastatic cancer (esp. breast, lung, prostate, gastric), tuberculosis, histoplas mosis and SLE. See Table 7.7. PMF is \210\222ve for Ph chromosome and BCR-ABL fusion gene. \200 Metastatic cancer in m arrow, especially breast, prostate, and thyroid, can give similar FBC features but without splenomegaly; metastatic carcinoma cells are usually apparent on marrow biopsy and/or aspir ate. Prefi brotic stage may be diffi cult to distinguish from PV/ET; prominent neutrophil prolif eration, reduced erythroid precursors and particularly the markedly abnormal megakaryocytes assist in correct diagnosis. Table 7.7 Conditions associated with BM fi brosis13 Hematological disorders Non-hematological disorders PMF \200 PV \200 CML \200 ET \200 AML (AML-M7) \200 Myelodysplastic syndromes \200 CMML \200 ALL \200 HCL \200 Hodgkin lymphoma \200 Non-Hodgkin lymphoma \200 MM \200 CEL \200 Mast cell disease \200 Malignant histiocytosis Metastatic cancer (breast, lung, prostate, gastric) Autoimmune myelofi brosis \200 Systemic lupus erythematosus \200 Kala-azar (leishmanias is) \200 Tuberculosis \200 Histoplasmosis \200 Paget disease \200 HIV infection \200 Vitamin D-resistant rickets \200 Renal osteodystrophy \200 Hyperparathyroidism \200 Gray platelet syndrome \200 Familial infantile myelofi brosis \200 Radiation expo sure \200 Osteopetrosis Diagnostic criteria The 2008 revised WHO diagnostic criteria for PMF defi ne 3 major and 4 minor criteria and require all 3 major criteria plus 2 minor criteria for the diagnosis of PMF (Table 7.8).14 Prognostic factors Adverse prognosis is associated with: \200 Marked anemia. Hb<100 g/L i s signifi cant prognostic marker. \200 Older age. \200 WBC count. \200 Number of blas ts in peripheral blood. \200 Constitutional symptoms. \200 Abnormal karyotype (other th an 13q \210\222 or 20q \210\222); strongest predictor of poor survival in post-PV MF and post-ET MF.15 High CD34+ cell count. \200 Presence of JAK2-V617F mutation. 296 CHAPTER 7 Myeloproliferative neoplasms Table 7.8 2008 WHO diagnostic criteria for PMF14 Major criteria 1. Megakaryocyte proliferation and atypiaa accompanied by either retuculin a nd/or collagen fi brosis, or In the absence of reticulin fi brosis, the megakaryocyte changes must be accompanied by i marrow cellularity, granulocytic proliferation, and often i erythropoiesis (i.e. pre-fi b rotic PMF) 2. Not meeting WHO criteria for CML, PV, MDS, or other myeloid neoplasm 3. Demonstration of JAK2-V617F or other clonal marker (e.g. MPL-W515K/L) or No evidence of reactive marrow fi brosis Minor criteria 1. Leucoerythroblastosis 2. i serum LDH 3. Anemia 4. Palpable splenomegaly a Small-to-large megakaryocytes with an aberrant nuclear/cytoplasmic ratio and hyperchromat ic and irregularly folded nuclei and dense clustering. Risk assessment Risk assessment has become important to identify patients for whom the risk s of SCT are appropriate. A number of systems have been devel- oped but none is clearly sup erior. The simple Lille scoring system (Table 7.9) is based on 2 adverse prog- nostic factors has been widely used in both PMF and post-PV/ET MF.15 Prognostic scoring systems Lille prognostic scoring system Two factors: \200 Hb <100 g/L. \200 WBC <4 \227 109/L or >30 \227 109/L. Table 7.9 Lille prognostic scoring system for MF Number of factors Risk group Cases (%) Median survival (months) 0 Low 47 93 1 Intermediate 45 26 2 High 8 13 International Prognostic Scoring System (IPSS)16 \200 5 risk factors for estimating survi val from time of diagnosis: \200 Age >65 years. \200 Hemoglobin level <100 g/L. \200 Leucocyte count >25 \227 109/L. \200 Circulating blasts \211 1%. \200 Presence of con stitutional symptoms. 297 PRIMARY MYELOFIBROSIS See Table 7.10. Table 7.10 IPSS for PMF16 Number of factors Risk group Expected median survival (years) 0 Low 11.3 1 Intermediate 1 7.9 2 Intermediate 2 4.0 \211 3 High 2.3 Dynamic IPSS-plus (DIPSS-plus) \200\224modifi ed IPSS for use at any time during the disease course.17,18 See Table 7.11. Table 7.11 DIPPS-plus prognostic scoring system17,18 Prognostic variable 0 1 Age (years) \211 65 >65 WBC \211 25 >25 Hb (g/L) \211 100 <100 PB blasts (%) <1 \211 1 Constitutional symptoms No Yes RC transfusion need No Yes Platelet count <100 Unfavorable karyotypea \211 100 <100 No Yes a Complex karyotype or sole or 2 abnormalities that include +8, \210\2227/7q \210\222, i(1 7q), inv(3), \210\2225/5q \210\222, 12p \210\222, or 11q23 rearrangement. The 8 DIPSS-plus risk factors are used to defi ne low (no risk factors), intermediate 1 (1 risk factor), intermediate 2 (2 or 3 risk factors), and high ( \211 4 risk factors) -risk groups with respective median survivals of 15.4, 6.5, 2.9, and 1.3 years. Management \200 PMF is incurable except by allogeneic SCT but few patients are eligible; no other treatment is currently proven to alter disease course, prevent leukaemic transform ation, or prolong survival. However, results from ongoing trials with novel agents such as JAK2- inhibitors (ruxolitinib) are awaited. Treatment is largely palliative and aims to improve anemia, alleviate symptomatic organomegaly, and hypercatabolic symptoms. Asymptomatic cases with minimal FBC abnormalities and splenic enlargement should simply be observed with regular follow-up. Allopurinol should be commenced to treat or prevent hyperuricaemia. 298 CHAPTER 7 Myeloproliferative neoplasms Treatment of anemia \200 Treatment for anemia should be considered at Hb <10g/dL, in symptomatic patients and those with reduced functional capacity.19 \200 Red cell transfus ion for symptomatic anemia; transfuse on basis of symptoms not at a specifi c Hb level; Fe chelation therapy should be initiated when long-term transfusion therapy is commenced. Androgen therapy: semi-synthetic androgen danazol commenced at a dose of 200mg tds, tapering to minimum eff ective dose in responders after 6 months improve s Hb in 740%;20 median time to response 5 months; most respond within 2 \200\2233 months, s ome later (6 \200\2239 months); response usually transient; fewer side eff ects than other androgens, e.g. oxymetholone; frequent slight i in LFTs and androgenic eff ects in \231 \200; monitor LFTs; may have synergistic eff ect with EPO.21 Continues to be used in treatm ent of anemia in PMF. Corticosteroids: prednisolone (1mg/kg/d) primarily indicated for PMF patients with DAT+ haemolysis.19 EPO: rHuEPO at initial dose of 10,000 units 3 \227 weekly achieves responses in 40 \200 \22350% of patients which may be maintained >12 months in half;21,22 Darbepoetin alfa at in itial dose 150mcg/week rising to 300 mcg/week if no response after 4 \200\2238 weeks achiev es similar response rate;23 serum EPO level <125 U/L increases the probability of response; EPO recommended in treatment of PMF- associated anemia in patients unresponsive to danazol or in whom it is inappropriate;19 alternatively if serum EPO inadequate give trial of rHuE PO/darbepoetin for 3 months and continue in responders. Cytoreductive therapy \200 Controls proliferative features (leucocytosis, thrombocytosis, splenomegaly, and constitutional symptoms); no eff ect on disease course; can worsen anemia . Hydroxycarbamide (HC): cytoreductive therapy of choice;19 usually promptly reduces leucocytosis, thrombocytosis, and hypercatabolic symptoms; splenomegaly re sponse may take several months; commence at 15 \200\22320mg/kg/d and titrate to maintain no rmal counts; generally well tolerated apart from worsening anemia. Cytotoxic alternatives to HC: low-dose melphalan (2.5mg tiw) and busulfan (2mg/d for 1 \200 \2232 months at 3 \200\2236-month intervals) can normalize counts and reduce splenomegaly b ut are associated with higher rates of leukaemic transformation up to 30%. Only used in eld erly patients and palliative situations. Cladribine (2-CDA): recommended in symptomatic patients refractory to other therapies;19 al so useful for management of thrombocytosis, leucocytosis, and progressive hepatomegaly afte r splenectomy;24 dose 0.05 \200\2230.1mg/kg for 7d per month for up to 5 cycles. Interferon alfa: 5 million units tiw controls hyperproliferative features but poor toleranc e limits its utility.25 Has been recommended for younger patients. Anagrelide: may control thrombocytosis in patients intolerant of other cytoreductive therapy but no impact on myelofi brosis. 299 PRIMARY MYELOFIBROSIS Anti-angiogenic agents \200 Thalidomide: at low dose (50mg/d) in combination with prednisolone (0.5mg/kg/d) can improve anemia (in up to 70%), thrombocytopenia (in up to 75% ), and reduce spleen size (in 19%);26 higher doses of thalidomide are poorly tolerated and benefi t has been diffi cult to demonstrate; low-dose thalidomide + prednisolone is recomme nded in non-responders to danazol and EPO.19 Lenalidomide: (10mg/d for 3 \200\2234 months) can improve anemia (22%), thrombocytopenia (5 0%), and splenomegaly (33%)27 and reduce cells bearing marker chromosomes and JAK2-V617F.28 Splenectomy \200 Palliative measure indicated for massive or symptomatic splenomegaly, excessive transfusion requirements, refractory thrombocytopenia, hypercatabol ic symptoms unresponsive to cytoreduction, uncontrollable haemolysis, and portal hypertensi on. Evaluate coagulation system preoperatively; contraindicated in patients with thrombocytosis \200\224control preoperatively. A review of 314 patients treated from 1976 \200\2232004 reports 7% operative mortality, 28% perioperative morbidity (infection, thrombosis, bleeding), 76% symptomatic improvement, 50 % improvement in anemia, and 19-month median overall survival; survival was reduced in pati ents with preoperative thrombocytopenia <100 \227 109/L; post-splenectomy thrombocytosis o ccurred in 29% and accelerated hepatomegaly in 10%; perioperative thrombo- haemorrhagic com plications were d by prompt use of cytoreductive agents.29 No evidence that splenectomy is followed by an i risk of leukaemic transformation. Radiotherapy \200 Splenic irradiation may be used to reduce spleen size and discomfort in patients unfi t for splenectomy (3 \200\2236-month benefi t);30 due to transient benefi t and the risk of severe pancytopenia (745%), not recommended for most patients; irradiation pre-splenectomy increases risk of post-op bleeding. Hepatic irradiation contraindicated due to same problems. \200 Low-dose involved fi eld i rradiation is useful treatment for extramedullary haemopoietic (EMH) infi ltrates at other sites, e.g. paraspinal, pericardium , pleural, or peritoneal cavities (causing eff usion or ascites) and whole lung irradiation is eff ective when pulmonary EMH causes pulmonary hypertension.13,25 Allogeneic SCT \200 Only therapy for PMF with curative potential; consider in all patient s \211 65 years with high-risk features at diagnosis or later in the disease course. Myeloablative conditioning regimens have been associated with high transplant-related mortality (25 \200\22348%).31 Advanced age is an important prognostic factor in myeloablative SCT: 14% patients \211 45 years survived at 5 years vs 62% younger patients.32 300 CHAPTER 7 Myeloproliferative neoplasms RIC conditioning with cyclophosphamide + busulfan appears to give better outcomes than TBI- based conditioning regimens due to lower toxicity. Myeloablative SCT may be expected to achieve 33 \200\22353% CR rate, 27 \200\22348% TRM at 1 year and 41 \200\22364% OS between 2.8 \200\2235 years (reviewed in reference 31). Reduced-intensity conditioning (RIC) reduces toxicity in older patients including those with unrelated donors; the 2 largest studies each with 21 patients with median age 754 years, reported CR in 775%, 10 \200\22316% TRM at 1 year, and 785% OS between 2.2 \200\2232.7 years. The optimum RIC regimen has not been established. \200 The place of splenectomy before SC T is unclear though it may be associated with more rapid hematological reconstitution. Responses to donor lymphocyte infusions (DLI) in patients who have relapsed after allo-SCT have been reported.25 Myeloablative or RIC SCT is indicated in patients with high-risk PMF aged <45 years; RIC SC T should be considered in patients suitable for intensive therapy with high-risk PMF aged 4 5 \200\22365 years; RIC SCT should be considered in patients with intermediate risk PMF on an individual basis. JAK2-inhibitors33,34 \200 Ruxolitinib is approved for use in PMF in the USA and UK (via the national Cancer Drug Fund). Oral agent; well tolerated. Impressive clinical/symptomatic res ponse though no change in disease course documented as yet. Trials ongoing. Novel therapies31,33,34 \200 Other JAK2 inhibitors: partial or complete resolution of spl enomegaly and reduction in constitutional symptoms. Bortezomib, the proteasome inhibitor that inhibits NF B remains in early phase trials in PMF. Azacitidine and decitabine are hypomethylating agents in early phase studies as single agen ts or in combination with a histone deacetylase inhibitor. Inhibitors of vascular endothelial growth factor (VEGF) remain in early phase trials. Pomalidomide remains investigational. Prognosis \200 Worst prognosis of the MPNs: median survival 3.5 \200\2235 years (range 1 \200\22330 years). Morbidity and mortality commonly due to leukaemic transformation, portal hypertension, infection, hemorrhage, and thrombosis. Hypersplenism often develops as the spleen enlarges. \200 Progressive cachexia occurs due to hypercatabolic state in advanced PMF. Death in symptomatic cases usually due to infection or hemorrhage. \200 Up to 20% transfo rm to AML refractory to intensive chemotherapy. 301 PRIMARY MYELOFIBROSIS References 1. Baxter, E.J. et al. (2005). Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet, 365, 1054 \200\22361. 2. Scott, L.M. et al. (2006). Progenitors homozygous for the V617F JAK2 mutation occur in m ost patients with polycythemia vera, but not essential thrombocythemia. Blood, 108, 2435 \200\2237. 3. Mesa, R. et al. (2006). A longitudinal study of the JAK2V617F mutation in myelofi brosis with myeloid metaplasia: analysis at two time points. Haematologica, 91, 415 \200\2236. 4. Campbell, P.J. et al. (2006). V617F mutation in JAK2 is associated with poorer survival in idiopathic myelofi brosis. Blood, 107, 2098 \200\223100. 5. Teff eri, A. et al. (2006). Respective clustering of unfavorable and favorable cytogenet ic clones in myelofi brosis with myeloid metaplasia with homozygosity for JAK2V617F and res ponse to erythropoietin therapy. Cancer, 106, 1739 \200\22343. 6. Pardanani, A.D. et al. (2006). MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 118 patients. Blood, 108, 3472 \200\2236. 7. Lasho, T.L. et al. (2006). Concurrent MPL515 and JAK2V617F mutations in myelofi brosis: chronology of clonal emergence and changes in mutant allele burden over time. Br J Haematol , 135, 683 \200\2237. 8. Guglielmelli, P. et al. (2007). GIMEMA \200\223Italian Registry of Myelofi brosis; MPD Research Consortium. Anemia characterizes patients with myelofi brosis harboring Mpl mutation. Br J Haematol, 137, 244 \200\2237. 9. Al-Assar, O. et al. (2005). Gains on 9p are common genomic aberrations in idiopathic mye lofi brosis: a comparative genomic hybridization study. Br J Haematol, 129, 66 \200\22371. 10. Dong, M. and Blobe, G.C. (2006). Role of transforming growth factor-beta in hematologic malignancies. Blood, 107, 4589 \200\22396. 11. Massa, M. et al. (2005). Circulating CD34+, CD133+ and vascular endothelial growth fact or receptor 2-positive endothelial progenitor cells in myelofi brosis with myeloid metaplas ia. J Clin Oncol, 23, 5688 \200\22395. 12. Thiele, J. et al. (2001). Clinical and morphological criteria for the diagnosis of pref i brotic idiopathic (primary) myelofi brosis. Ann Hematol, 80, 160 \200\2235. 13. Teff eri, A. and Barbui, T. (2005). bcr/abl \200\223negative, classic myeloproliferativ e disorders: diagnosis and treatment. Mayo Clin Proc, 80, 1220 \200\22332. 14. Teff eri, A. and Vardiman, J.W. (2008). Classifi cation and diagnosis of myeloprolifera tive neoplasms: The 2008 World Health Organization criteria and point-of-care diagnostic al gorithms. Leukemia. 22, 14 \200\22322. 15. Dupriez, B. et al. (1996). Prognostic factors in agnogenic myeloid metaplasia: a report on 195 cases with a new scoring system. Blood, 88, 1013 \200\2238. 16. Cerbantes, F. et al. (2009). New prognostic scoring system for primary myelofi brosis b ased on a study of the International Working Group for Myelofi brosis Research and Treatmen t. Blood, 113(13), 2895 \200\223901 17. Passamonti, F. et al. (2010). A dynamic prognostic model to predict survival in primary myelofi brosis: a study by the IWG-MRT (International Working Group for Myeloprolif erative Neoplasms Research and Treatment). Blood, 115(9), 1703 \200\2238. 18. Gangat, N. et al. (2011). DIPSS-Plus: a refi ned Dynamic International Prognostic Scori ng System (DIPSS) for primary myelofi brosis that incorporates prognostic information from karyotype, platelet count and transfusion status. J Clin Oncol, 29(4), 392 \200\2237. 19. Nordic MPD Study Group (2007). Guidelines for the diagnosis and treatment of patients w ith polycythemia vera, essential thrombocythemia and idiopathic myelofi brosis. M www. sfhe m.se/fi larkiv/fi les/vardprogram/NMPDGuidelines2007.pdf 20. Cervantes, F. et al. (2005). Effi cacy and tolerability of danazol as a treatment for t he anemia of myelofi brosis with myeloid metaplasia: long-term results in 30 patients. Br J Haematol, 129, 771 \200\2235. 21. Hasselbalch, H.C. et al. (2002). Successful treatment of anemia in idiopathic myelofi b rosis with recombinant human erythropoietin. Am J Hematol, 70, 92 \200\2239. 22. Cervantes, F. et al. (2004). Erythropoietin treatment of the anemia of myelofi brosis w ith myeloid metaplasia: results in 20 patients and review of the literature. Br J Haematol, 127, 399 \200\223403. 23. Cervantes, F, et al. (2006), Darbepoetin-alpha for the anemia of myelofi brosis with my eloid metaplasia. Br J Haematol, 134, 184 \200\2236. 24. Faoro, L.N. et al. (2005). Long-term analysis of the palliative benefi t of 2-chlorodeo xyadenosine for myelofi brosis with myeloid metaplasia. Eur J Haematol, 74, 117 \200\22320. 302 CHAPTER 7 Myeloproliferative neoplasms 25. Arana-Yi, C. et al. (2006). Advances in the therapy of chronic idiopathic myelofi brosi s. Oncologist, 11, 929 \200\22343. 26. Mesa, R.A. et al. (2003). A phase 2 trial of combination low-dose thalidomide and predn isone for the treatment of myelofi brosis with myeloid metaplasia. Blood, 101, 2534 \200\22341. 27. Teff eri, A. et al. (2006). Lenalidomide therapy in myelofi brosis with myeloid metapla sia. Blood, 108, 1158 \200\22364. 28. Teff eri, A. et al. (2007). Lenalidomide therapy in del(5)(q31)-associated myelofi bros is: cytogenetic and JAK2v617F molecular remissions. Leukemia, 108, 1158 \200\22364. 29. Mesa, R.A. et al. (2006). Palliative goals, patient selection and perioperative platele t management: outcomes and lessons from 3 decades of splenectomy for myelofi brosis with myel oid metaplasia at the Mayo Clinic. Cancer, 107, 361 \200\22370. 30. Elliot, M.A. et al. (1998). Splenic irradiation for symptomatic splenomegaly associated with myelofi brosis with myeloid metaplasia. Br J Haematol, 103, 505 \200\22311. 31. Hoff man, R. and Rondelli, D. (2007). Biology and treatment of primary myelofi brosis. Hematology, 2007, 346 \200\223354. 32. Guardiola, P. et al. (2000). Myelofi brosis with myeloid metaplasia. N Engl J Med, 343, 659. 33. Teff eri, A. (2011). How I treat myelofi brosis. Blood, 117, 3494 \200\223504. 34 . Verstovsek, S. et al. (2013). The clinical benefi t of ruxolitinib across patient subgrou ps: analysis of a placebo-controlled, Phase III study in patients with myelofi brosis. Br J Hae matol, 161(4), 508 \200\22316. Further reading Swerdlow, S.H. et al. (2008). WHO Classifi cations of Tumors of Haematopoie tic and Lymphoid Tissues, 4th ed. Lyon: IARC. 303 PRIMARY MYELOFIBROSIS 304 CHAPTER 7 Myeloproliferative neoplasms Chronic neutrophilic leukemia \200 Characterized by peripheral blood mature neutrophilia ( \211 25 \227 109/L) without signifi cant left shift, monocytosis, eosinophilia, or basop hilia.1 \200 Very rare; historically a minority fulfi l criteria for \200\230true \200 \231 CNL and this diagnosis has encompassed a number of distinct pathological entities.2 Median age 765 years, range 15 \200\22386; \231\202: \231\200 ratio 2:1.2 \200 Usually a symptomatic at diagnosis; fatigue most common symptom.3 \200 Blood tests: usually no anem ia or thrombocytopenia at presentation. \200 i serum B12 and i uric acid (and history of gout) common. Diagnostic criteria (WHO 2008) \200 Peripheral blood leucocytosis \211 25 \227 109/L wi th >80% neutrophils and bandforms and blasts <1%. Hypercellular BM with i granulocytes with normal maturation. Blasts <5%. Hepatosplenomegaly. \200 No identifi able cause for physiological neutrophilia, or demons tration of clonality. No Philadelphia chromosome or BCR-ABL1 fusion gene. \200 No rearrangement of PDGFRA, PDGF RB, or FGFR1. \200 No evidence for PB, ET or PMF. \200 No evidence of MDS or MDS/MPN. Prognosis Variable prognosis described for patients with CNL with survival up to 20 years.1 \200\230True \200\231 CNL may have median OS of 30 months with only 28% 5-year OS.2,3 \200 Disease acceleration: progressive treatment-refractory neutrophilia, marked splenomegaly, anemia, thrombocytopenia, and the appearance of immature myeloid proge nitors including blasts in the peripheral blood.3 A signifi cant proportion of patients with CNL will progress to AML. \200 Death due to bl ast transformation, progression without transformation, bleeding complications and infectio n. No standard treatment recommendation; optimum therapy undefi ned; Treatment may be unnecess ary if asymptomatic. Treatment \200 Hydroxycarbamide (HC) may control progressive neutrophilia and splenomegaly and maintain a prolonged stable phase; recommended 1st-line therapy with media n response of 12 months.3 Busulfan can achieve the same eff ect. \200 Interferon alfa is option as 2nd-line therapy 3 though responses to 2nd-line therapy often short-lived and poorly tolerated.4 AML-type induction therapy is ineff ective.4 \200 Splenic irradiation and splenectomy can reduce tumor bulk and relieve abdominal discomfort; splenectomy may aggravate leucocytosis.5 \200 Allogeneic SCT is pot entially curative5,6 and in view of the poor prognosis of patients with true CNL, should be considered in eligible patients. 305 CHRONIC NEUTROPHILIC leukemia References 1. Imbert, M. et al. (2001). Chronic neutrophilic leukemia. In Jaff e, E.S. et al. (eds.) Worl d Health Organization Classifi cation of Tumors. Pathology and Genetics. Tumors of Haematop oietic and Lymphoid Tissues, vol 1, pp. 27 \200\2238. Lyon: IARC Press. 2. Reilly, J.T. (2002). Chronic neutrophilic leukemia: a distinct clinical entity? Br J Hae matol, 116, 10 \200\22318. 3. Teff eri, A. et al. (2006). Atypical myeloproliferative disorders: diagnosis and treatme nt. Mayo Clin Proc, 81, 553 \200\22363. 4. Elliot, M.A. et al. (2001). Chronic neutrophilic leukemia (CNL): a clinical, pathologic and cytogenetic study. Leukemia, 15, 35 \200\22340. 5. Hasle, H. et al. (1996). Chronic neutrophilic leukemia in adolesence and young adulthood . Br J Haematol, 9, 628 \200\22330. 6. Pilotis, E. et al. (2002). Allogeneic bone marrow transplantation in the management of chronic neutrophilic leukemia. Leuk Lymphoma, 43, 2051 \200\2234. Further reading Swerdlow, S.H. et al. (2008). WHO Classifi cations of Tumors of Haematopoie tic and Lymphoid Tissues, 4th ed. Lyon: IARC. 306 CHAPTER 7 Myeloproliferative neoplasms Eosinophilic syndromes and neoplasms Persistent eosinophilia in the peripheral blood and ti ssues may occur in a heterogeneous group of conditions and requires investigation. First st ep is to exclude a 2 eosinophilia. If reactive causes have been excluded a clonal diagnos tic entity can be expected, or if none found, idiopathic hypere- osinophilic syndrome. The diagnostic entities historically were classifi ed as myeloproliferative disorders, though d istinct categories now exist.1 Diagnostic groups/entities (discussed here)1,2 \200 Reactive or 2 eosinophilia. \200 Myeloid and lymphoid neoplasms with abnormalities of PDGFRA, PDGFRB, or FGFR1. Chronic eosinophilic leukemia, not otherwise specifi ed (CEL, NOS). \200 Lymphocyte-varia nt hypereosinophilia. \200 Idiopathic hypereosinophilic syndrome (HES), which is a diagno sis of exclusion. Investigation of a patient with eosinophilia All patients with eosinophilia should be asses sed with a detailed history including drugs and travel, a full physical examination, blood count and fi lm, routine chemistry, serum IgE, serum B12, ECG, echocardiogram, CXR, pul- mo nary function tests, and CT chest and abdomen. Further investigations may be indicated by t he fi ndings, e.g. parasite screen, HIV serology. If eosinophilia remains unexplained, the diagnostic algorithm recom- mended by Teff eri and Vardiman1 and based on the 2008 WHO criteria should be used: \200 Perform BM biopsy, try ptase stain, T-cell clonality studies (immunophenotyping and TCR gene rearrangement studies), cytogenetic studies, and FISH or RT -PCR for FIP1L1-PDGFRA: \200 FIP1L1-PDGFRA +ve l PDGFRA rearranged myeloid neoplasm with eosinophilia. 5q33 translocations l PDGFRB rearranged myeloid neoplasm with eosinophilia. 8p11 translocations l FGFR1 rearranged myeloid neoplasm with eosinophilia. BM histology shows abnormalities other than eosinophilia l use histology to make specifi c diagnosis BM unremarkable other than eosinophilia and no clonal T cells \200\223 l PB blasts >2% or BM blasts >5% or abnormal cytogenetics: CEL-NOC/HES. \200\223 l PB blasts <2% and BM blasts <5% and no abnormal cytogenetics: idiopathic HES . 307 EOSINOPHILIC SYNDROMES AND NEOPLASMS Conditions associated with 2 or reactive eosinophilia \200 Allergic: asthma, allergic b ronchopulmomary aspergillosis, drug reactions. \200 Infectious and parasitic: helminths, ectoparasites (scabies), protozoa, fungi (coccidiomycosis), mycobacteria, and viruses (HIV, HSV). \200 Infl ammatory: Loeffl er syndrome, collagen vascular disorders (Wegener granulomatosis, PAN, SLE), sarcoid. Neoplastic: CML, AML with inv(16), ALL, angioimmunoblastic lymphoma, chronic MPNs, Hodgkin and non-Hodgkin lymphoma, adenocarcinoma. Immune dysregulation: Wiskott \200\223Aldrich syndrome, phenotypically aberrant T lymphocytes with abnormal release of cytokines. Metabolic: hypoadrenalism. Myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FG FR1 The 2008 WHO classifi cation1 has redefi ned myeloid and lymphoid neoplasms with molecu larly characterized clonal eosinophilia, previously classifi ed under CEL/HES, as a new cat egory of their own and removed them from the MPN category. Myeloid and lymphoid neoplasms associated with PDGFRA rearrangement (platelet derived growt h factor) \200 Rare disorder. Karyotype usually normal. \200 Activating mutation of the gene for PDGFRA due to interstitial deletion at 4q12 producing a FIP1L1-PDGFRA fusion gene.3 Associated with HES, CEL, and syst emic mastocytosis (SM).3 \200\2235 t(4;22)(q12;q11) producing BCR-PDGFRA fusion gene also described associated with atypical CML.6 FIP1L1-PDGFRA detected by FISH in 14% of patients with \200\230primary eosinophilia \200\231; also detectable by RT-PCR; almost all classifi ed h istologically as SM due to mast cell infi ltrates in the BM.5 SM-CEL has been suggested as nomenclature.7 Occurs almost exclusively in \231\202; associated with eosinophil- related tissue damage, elevated serum tryptase, splenomegaly, BM hypercellularity with reti culin fi brosis, and atypical mast cells. Extremely sensitive to imatinib therapy: 100mg/d achieved 100% durable clinical and hematol ogical CR in 8 patients;8 if clinical or molecular relapse occurs, the dose should be i to 400mg/d;9 concomitant prednisolone therapy (1mg/kg/d) is recommended for initial 1 \200\223 2 weeks to reduce risk of drug-induced cardiogenic shock.7 Acute phase disease may be myeloid or T-lymphoblastic. Myeloid neoplasms associated with PDGFRB rearrangement (platelet derived growth factor) \200 Rare disorder. \200 Activating mutation of PDGFRB gene at 5q33 associated with eosinophilia sometimes accompanied by monocytosis.10 Usually involves translocation e.g. t(5;12)(q33;p13) and karyotype usually abnormal. Detected in patients previously diagnosed with CEL or CMML.11 \200 Rarely aff ects \231 \200; also responds to imatinib. 308 CHAPTER 7 Myeloproliferative neoplasms