IgM Paraprotein-Associated Type 1 Cryoglobulinaemia: Clinical Characteristics and Outcomes

Introduction

Type 1 cryoglobulinaemia (CG) is characterised by monoclonal immunoglobulins which precipitate at temperatures below 37°C and redissolve on warming. They may be associated with lymphoproliferative disorders including Waldenström's macroglobulinemia (WM), other non-Hodgkin lymphoma (NHL), chronic lymphocytic leukaemia (CLL) or monoclonal gammopathy of undetermined significance (MGUS). Due to their rarity and heterogeneous clinical manifestations, incidence and outcomes are not well characterised and they are likely underdiagnosed. We retrospectively reviewed our cohort of patients (pts) with IgM paraprotein-associated type 1 CG.

Methods

Data from consecutive pts during 2013 and 2021, aged >18 years were extracted from clinical databases at two specialist centres [UCLH, United Kingdom (UK) and AMC, Netherlands].

Results

A total of 62 pts (38 male, 24 female) were identified (Table 1); 59 from UK and 4 from Netherlands: 49 (79%) had WM, 7 (11%) IgM MGUS and 6 (10%) NHL (5 other lymphoma, 1 CLL). Median age at CG diagnosis was 66 (range 39-90) years; 32 (52%) were >65 years. MYD88 was mutated in 23/25 (92%) evaluable cases of WM. All cases were negative for hepatitis C.

CG was detected after the monoclonal disorder in 46 (74%), with a median time to CG diagnosis of 8 (range 0-1390) months, concurrently in 11 (18%) pts and at a median of 1 month (range 0-4) in 5 (8%) pts prior to the monoclonal disorder. These patients were diagnosed due to CG symptoms. Eight pts (of which 50% had WM) also had active cold agglutinin disease (CAD).

CG symptoms were present at time of testing in 25 (40%) pts; the others were diagnosed as a part of asymptomatic screening. CG symptoms were more common in those with MGUS / NHL compared to WM, most frequently in MGUS compared to WM (33% v 71%, p=0.05). Skin manifestations including acrocyanosis, purpura, ulcer and necrosis were noted in 14 (23%); 11 (18%) had peripheral neuropathy (6 sensory, 5 mixed) and 8 (13%) hyperviscosity. Median plasma viscosity was >7 (range 4.7 - >7) mPa of 5/8 pts measured with hyperviscosity and a median paraprotein of 29 (range 5-63) g/l. One patient with WM had cryoglobulinaemic glomerulopathy demonstrated by renal biopsy.

In all, 53 (85%) pts received treatment, 10 (16%) for the CG and 43 for the monoclonal disorder, including plasma exchange (11/53). Thirty had Rituximab-based therapy (Table 1), and one received Ibrutinib. All achieved complete resolution of symptoms and 3/6 (50%) treated for CG had complete biochemical response with cryoglobulins undetectable after treatment. Two (20%) required further lines of therapy >4 years later. Overall at a follow up of 21 (range 0-94) months, median survival was not reached. Nine (14%) pts died, with 1 (2%) CG-related death due to relapse disease. Estimated 5-year overall survival (OS) was 67% (95% CI 40-84%) (figure 1).

Conclusions

In our cohort of 62 pts with type I IgM paraprotein-associated CG, the majority had WM compared to other NHL and MGUS, likely reflecting the clinical bias of the centres and our policy of screening for CG at first visit. A greater proportion of cases (40%) were symptomatic than previous reports (16%; Néel et al, 2014); when present, symptoms were dominated by skin manifestations, neuropathy and hyperviscosity. Patients tested for CG with IgM MGUS were more likely to be symptomatic compared to WM. CAD co-existed in a proportion. Those with CG symptoms treated had good clinical responses; treatment subgroups were too small to draw conclusions as to relative efficacy, but Rituximab-based therapy appeared effective in most cases. CG-related mortality was low with an estimated 5-year OS 67%.

Figure 1

View largeDownload slide

Figure 1

View largeDownload slide

Close modal