sign in sign up
<<
Home , Cryoglobulinemia, Heavy chain disease, POEMS syndrome

The “other” paraproteinemias BHS course 06/05/2017

Ph. Vlummens Ghent University Hospital Outline presentation

• Solitary plasmocytoma • • POEMS syndrome • Solitary plasmocytoma

• The presence of 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 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 , 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 (MM, MW, CLL)

Mouchtar, Blood, 2017 Cryoglobulinemia : Classification

• Type II : Mixed character of globulins – Mix of monoclonal IgM and polyclonal IgG – Monoclonal IgM has activity – Associated diseases: • Most patients have virus (up to 90%) • Other: – Infectious : 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, , 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) ≈ 70% ≈ 90% Skin ulcers ≈ 30% ≈ 15% Glomerulonephritis ≈ 30% ≈ 30% ≈ 30% ≈ 30% Artralgia ≈ 30% ≈ 25% - 40% Organ involvement (, Almost never Rare, ≈ 5% heart, GI tract, CNS) Hyperviscosity syndrome Occasionally; usually in IgM Rarely; never in type III 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

• 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 ! • 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 : 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 24-78 Peripheral 24-89 22-70 7-54 Lymfadenopathy 26-74 3-43 CD 11-25 1-64 Endocrinopathy 67-84 Bone lesions 27-97 Gonadal axis 55-89 Thrombocytosis 54-88 Adrenal axis 16-33 12-19 Raised 5-20 Clubbing 5-49 Gynaecomastia 12-18 Decrease in DLCO >15 Diabetes mellitus 3-36 36 9-67 Weigth loss 37 Plasmaceldyscrasia 100 Fatigue 31 M-prot on SPEP 24-54 Skin changes 68-89 46-93 19 Hemangiomata 9-35 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 • 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 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 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., , 2017 Soubrier et al., 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?

• (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. 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 Malig Rep, 2017; Misawa et al., Lancet Neurol, 2016; Vannata et al., Am J Hematol, 2012; Jaccard et al., Blood, 2014; Zagouri et al., Leuk , 2014 Heavy chain diseases

• HCDs are rare B-cell lymphoproliferative disorders – Production of M-protein = portion of Ig heavy chain without a bound light chain – Often incomplete/truncated and a sharp M-peak can be absent of SPEP or UPEP • Is not the same as heavy chain deposition disease – Nephrotic syndrome, hematuria and hypertension, progressive renal failure with or without the complication of . • Three subtypes : alfa/gamma/mu • Clinical presentation resembles low grade B-cell lymphoma

Oe et al., Clin Exp Nephrol, 2013; Wahner-Roedler DL et al., Best Pract Res Clin Haematol, 2005 Heavy chain diseases

• Alpha HCD = form of mucosa associated lymphoid tissue (MALT) lymphoma (Seligmann disease) • Gamma HCD = typically associated with presence of systemic lymphoma (Franklin’s disease) • Mu HCD = features resembling SLL/CLL, distinctive lymphocytes/PCs in bone marrow Diagnosis

• Based on histopathologic examination of affected tissue – Clonal population of cells staining positively for alpha/gamma/mu heavy chain • SPEP and UPEP with immunifixation (variable) – Aberrant presentations due to truncated forms • Absence of associated light chain

Bianchi et al., , 2014; Wahner-Roedler DL et al., Best Pract Res Clin Haematol, 2005 Alpha HCD : Clinical presentation and therapy

• Most common form, usually young males, poor sanitation • Middle-East region, Mediterranean region • GI tract involvement (jejunal infiltration of plasmacytoid cells), resulting in abdominal pain, malabsorption,

• Fatal in absence of therapy • Treatment : antibiotics, chemotherapy (R)CHOP in non- responders

Bianchi et al., Oncology, 2014; Gamma HCD : Clinical presentation and therapy

• Median age at presentation is 60-70 years • Median OS 7,4 years (1 month – 21 years) • Presence of systemic symptoms, , splenomegaly • Occasionally also palatal and uvular swelling • Can be indolent or aggressive • Auto-immune manifestations in 1/3 of patients (ITP, HA, vasculatis, SLE, RA)

• Treatment only in symptomatic patients • Chemotherapy CVP/CHOP with/without R (CD20 pos) • Varying success in patients requiring therapy

Bianchi et al., Oncology, 2014; Wahner-Roedler DL et al., Best Pract Res Clin Haematol, 2005 Mu HCD : Clinical presentation and therapy

• Least common form • SLL/CLL phenotype (less peripheral adenopathy) • Presence of vacuolated lymphocytes/PCs in bone marrow • Survival ranges from few months to many years

• Treatment reported in literature incl. fludarabine, R- fludarabine, (R-)CHOP, CLL-based

Bianchi et al., Oncology, 2014; Wahner-Roedler DL et al., Best Pract Res Clin Haematol, 2005 Selected references

• Plasmocytoma: – Finsinger et al., Clinical features and prognostic factors in solitary plasmocytoma. Brit J Hematol 2015;172 • Cryoglobulinemia: – Muchtar et al., How I treat cryoglobulinemia. Blood 2017;129(3) • POEMS: – Warsame et al., POEMS syndrome: an enigma. Curr Hematol Malig Rep, 2017 – Dispenzieri, POEMS syndrome: update on diagnosis, risk-stratification, and management. Am J Haematol 2015;215:951-62 • HCD: – Bianchi et al., The heavy chain diseases: clinical and pathologic features. Oncology (Williston Park) 2014;28(45)