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The “Other” Paraproteinemias BHS Course 06/05/2017

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The “Other” Paraproteinemias BHS Course 06/05/2017 The “other” paraproteinemias BHS course 06/05/2017 Ph. Vlummens Ghent University Hospital Outline presentation • Solitary plasmocytoma • Cryoglobulinemia • POEMS syndrome • Heavy chain disease Solitary plasmocytoma • The presence of plasma cell proliferation in one site without evidence of systemic involvement/CRAB • Two entities: – Solitary plasmocytoma of bone – Extramedullary plasmocytoma Finsinger, Brit J Hematol, 2015 Solitary plasmocytoma • Accounts for max. 5% of all plasma cell neoplasms diagnosed annually • Incidence 0,15/100.000 patient-years (US) • Median age at diagnosis 55 – 63 years • Male/female : 62,4 vs 37,6% • Overall survival 78,4% at 5 years (SPB <> EMP) Finsinger, Brit J Hematol, 2015 SEER database 1998 - 2007 Site (total = 1691) Amount (% of total) Bone 977 (57,78) Axial skeleton 831 (49,14) Appendicular skeleton 146 (8,63) Extramedullary plasmocytoma 540 (31,93) Upper airway tract 211 (12,48) Lower airway tract 54 (3,19) GI tract 49 (2,9) Soft tissue and connective tissue 77 (4,55) CNS 49 (3,19) Lymph nodes 25 (1,48) Skin 20 (1,18) All other sites 55 (3,25) Unspecified 174 (10,29) Thumallapally, BMC Cancer, 2017 Solitary plasmocytoma : Clinical presentation Tumour consisting of sheets of atypical plasmacells Solitary plasmocytoma : Workup Kumar et al., JNCCN, 2017 Solitary plasmocytoma : Treatment Kumar et al., JNCCN, 2017 Solitary plasmocytoma : Evolution to MM • SEER database : 32,7% progressed to symptomatic MM • Difference between SBP and EMP – Finsinger et al. (2015) SBP EMP – Soutar et al. (2004) Predominant site Axial skeleten (vert) Head and neck % with M protein 60% <25% % developing MM > 75 < 25 • Patients who progress probably already have disseminated disease • Fouquet et al., 2014 : Importance of imaging (especially PET-CT) and FLC-ratio – Positive PET : OR 5 – Skewed FLC : OR 10 Soutar et al., British Journal of Hematology, 2004; Finsinger et al., BJH, 2015 Cryoglobulinemia • Presence of cryoglobulins in serum • Prevalence (US) 1/100000 • Ig precipitating at temp < body temp / 37°C • Clinical spectrum – Asymptomatic – End-organ damage due to precipitation in small/medium sized blood vessels • Classification into 3 subgroups Mouchtar, Blood, 2017 Cryoglobulinemia : Classification • Type I : Monoclonal character of globulins – IgG/IgM >> IgA/free immunoglobulin light chains – Develops in a setting of protein-secreting monoclonal gammopathies • 40% MGUS • 60% overt B-cell lineage malignancy (MM, MW, CLL) Mouchtar, Blood, 2017 Cryoglobulinemia : Classification • Type II : Mixed character of globulins – Mix of monoclonal IgM and polyclonal IgG – Monoclonal IgM has rheumatoid factor activity – Associated diseases: • Most patients have hepatitis C virus infection (up to 90%) • Other: – Infectious : Hepatitis B and HIV – Connective tissue disorders – Lymphoproliferative disorders • Up to 10% of patients do not have a attributable cause = essential mixed cryoglobulinemia Mouchtar, Blood, 2017 Cryoglobulinemia : Classification • Type III : Mixed character of globulines – Both IgM and IgG are polyclonal (<> type II) – Causes : • Connective tissue diseases • Infection (hepatitis C) Overall, cryoglobulins in mixed cryoglobulinemia result from a B-cell lymphoproliferative process in the setting of persistent immune activation triggered by chronic infection, autoimmune disease, or an unknown cause. Mouchtar, Blood, 2017 Cryoglobulinemia : Clinical spectrum Cryoglobulinemia : Clinical spectrum Cryoglobulinemia : Clinical spectrum Main clinical findings Type I Mixed (type II and III) Purpura ≈ 70% ≈ 90% Skin ulcers ≈ 30% ≈ 15% Glomerulonephritis ≈ 30% ≈ 30% Peripheral neuropathy ≈ 30% ≈ 30% Artralgia ≈ 30% ≈ 25% - 40% Organ involvement (lung, Almost never Rare, ≈ 5% heart, GI tract, CNS) Hyperviscosity syndrome Occasionally; usually in IgM Rarely; never in type III isotype and when M- protein > 4/dL Mouchtar, Blood, 2017 Cryoglobulinemia : Laboratory workup • Diagnosis = typical clinical features and presence of cryoglobulins • False-negative results! (sample handling) – Transfer and centrifuge at 37°C – Speed of precipitation • Type I : A few hours at 1° - 4°C • Mixed types : Delayed precipitation is possible – Contact your lab when a result is negative but the clinical suspicion is high! • Cryocrit can be useful – Relative volume of precipitate/total serum volume (%) – Higher levels type I (can be > 50%) > type II and III (<5%) – Poor correlation with disease activity and treatment response Mouchtar, Blood, 2017 Cryoglobulinemia : Laboratory workup • Immunofixation of the precipitate • RF and complement studies (C3, C4, CH50) Laboratory findings Type I Mixed (type II and III) Cryoglobulin composition Monoclonal Igs (usually IgG Monoclonal (type II) or or IgM) polycloncal (type III) IgM with RF activity and polyclonal IgG Cryocrit Above 5% Less than 5% Complement assays May be decreased Decreased (mainly C4) RF activity Occasionaly increased Increased Mouchtar, Blood, 2017 Cryoglobulinemia : Treatment • General considerations : – Treat symptomatic disease – Patient education (avoiding cold exposure, foot and leg care ie. diabetic foot care guidelines) • Type I: – Treat the underlying disorder (MM, WM, CLL) – Flare-up with rituximab! • Mixed type: Mouchtar, Blood, 2017 Cryoglobulinemia : Treatment Mouchtar, Blood, 2017 Cryoglobulinemia : Treatment Mouchtar, Blood, 2017 POEMS syndrome • Osteosclerotic myeloma, Crow-Fukase syndrome • Rare multisystemic disease (0,3/100000/y), acronym derived from the 5 main features: Polyneuropathy (usually demyelinating) Organomegaly Endocrinopathy Monoclonal protein (typically lambda, can be small) Skin changes • Sometimes referred to as POEMS-PEST : Papilledema Extravascular volume overload Sclerotic bone lesions Thrombocytosis/erythrocytosis Clinical spectrum at time of diagnosis Clinical sign % Clinical sign % Polyneuropathy 100 Papilledema 29-64 Organomegaly 45-85 Extravascular fluid overload 29-87 Hepatomegaly 24-78 Peripheral edema 24-89 Splenomegaly 22-70 Ascites 7-54 Lymfadenopathy 26-74 Pleural effusion 3-43 CD 11-25 Pericardial effusion 1-64 Endocrinopathy 67-84 Bone lesions 27-97 Gonadal axis 55-89 Thrombocytosis 54-88 Adrenal axis 16-33 Polycythemia 12-19 Raised prolactin 5-20 Clubbing 5-49 Gynaecomastia 12-18 Decrease in DLCO >15 Diabetes mellitus 3-36 Pulmonary hypertension 36 Hypothyroidism 9-67 Weigth loss 37 Plasmaceldyscrasia 100 Fatigue 31 M-prot on SPEP 24-54 Skin changes 68-89 Hyperpigmentation 46-93 Acrocyanosis 19 Hemangiomata 9-35 Hypertrichosis 26-74 Skin thickening 5-43 Dispenzieri, Am J Hematol, 2015 Cutaneous phenotype Miest et al., Int J Dermatol, 2013 Marinho et al., Case Rep Dermatol, 2015 Diagnostic criteria POEMS - PEST Confirmation of diagnosis when presence of: • Both mandatory criteria • One of the three other major criteria • One minor criteria Warsame et al., Curr Hematol Malig Rep, 2017 Dispenzieri, Am J Hematol, 2015 POEMS pathogenesis • Paraneoplastic phenomenon due to growth factors and cytokines • Implication of Vascular Endothelial Growth Factor (VEGF) – Binds to tyrosine kinase receptors – HIF transcription factor pathway • Also others have been implicated: – IL-6 – Tumor growth factor 1 beta – Tumor necrosis factor 1 alfa – IL-12 Warsame et al., Curr Hematol Malig Rep, 2017 POEMS pathogenesis from a clinical point of view VEGF dosing in POEMS syndrome • VEGF • Can be measured in serum and/or plasma • Different cut-off values for both assays (at diagnosis): • Serum : 1920 pg/mL • Plasma : 200 pg/mL – sensitivity 68% & specificity 95% • Levels are independent of M-protein size Warsame et al., Curr Hematol Malig Rep, 2017 Therapy for POEMS patients • Therapy should be chosen in function of the burden of disease – Patiënts with an isolated osteosclerotic lesion – Patiënts with systemic involvement (diffuse/>2 lesions or clonal plasmacells) • Isolated osteosclerotic lesion: radiotherapy (30 – 50 Gy) – Benefit on OS and PFS, 4-year OS 97% – Clinical response is seen in 47 – 75% and hematologisch response in 45 – 50% – No immediate benefit after RT, delay time can be up to or > 6 months (counseling) Suh et al., Radiat Oncol, 2014 Humeniuk et al., Blood, 2013 Therapy for POEMS patients • Therapy should be chosen in function of the burden of disease – Patiënts with an isolated osteosclerotic lesion – Patiënts with systemic involvement (diffuse/>2 lesions or clonal plasmacells) • Systemic disease – Autologous transplant (MEL200) or chemotherapy focussing on PCDs – Virtually all patients achieve some degree of response – As disease burden is generally low, no specific induction treatment is necessary (cave Li et al, 2017) – Induction therapy can however be used when a transpant isn’t feasible right away Kuwabara, Neurology, 2006; Li et al., Leukemia, 2017 Soubrier et al., Bone Marrow Transplant, 2002; Dispenzieri et al., Eur J Hematol, 2008 Therapy for POEMS patients Dispenzieri et al., Am J Hematol, 2015 Therapeutic effect • Delay in clinical response • Counseling is important • Supportive therapy – Pain management – Endocrinopathy – Fluid overload Warsame et al., Curr Hematol Malig Rep, 2017; Li et al., Leukemia, 2017 OS/PFS Li et al., Leukemia, 2017 Other therapies? • Bevacizumab (anti-VEGF) : No proven effect • IVIG : No proven effect • Tamoxifen, ATRA, interferon-alfa : Limited data from case reports • Ixazomib? • IMiDs? Seem to be usable ie. Lenalidomide in relapse setting • Case series, 12 pts : PFS/OS 2 years 92% • Systematic review / pooled analysis, 51 pts : PFS 93,9% and improvement of PNP in 92% Warsame et al., Curr Hematol
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