Type 1 Cryoglobulinaemia Associated with Waldenström Macroglobulinemia, IgM MGUS or Non-Hodgkin Lymphoma

Introduction: Type 1 cryoglobulinaemia is defined by monoclonal immunoglobulins which precipitate at temperatures <37°C and redissolve on warming. IgM monoclonal protein may be associated with type I cryoglobulinaemia with underlying Waldenström macroglobulinemia (WM), non-Hodgkin lymphoma (NHL) or monoclonal gammopathy of undetermined significance (MGUS). Due to its rarity, the incidence and clinical outcomes are poorly understood, with fewer than 40 patients characterised in the largest series. Clonal characteristics have not previously been described. We analysed the incidence, clinical and clonal characteristics of the largest reported series of IgM-associated type I cryoglobulinaemia.

Methods: Data for consecutive adult patients (> 18 years) with IgM-associated type I cryoglobulinaemia identified between 2013-2022 from 2 centres (University College London Hospital [UCLH], UK and AMC, Netherlands) were retrospectively analysed and followed up to June 2022. In order to calculate the incidence of type I cryoglobulinaemia, the total number of requests performed at UCLH was also determined.

Results: 423 samples were screened for cryoglobulinaemia between 2013-2022 from all patients with an IgM-associated disorder at the specialist centre, UCLH. 140 (33%) were positive for all-type cryoglobulinaemia; 94 (22%) patients had type I cryoglobulinaemia. Four additional patients were recruited from Amsterdam UMC, without incidence data. In total, 98 patients (58 male, 40 female) were identified with type I cryoglobulinaemia; the majority with underlying WM (defined as >10% bone marrow infiltration) (77; 79%), and remaining IgM MGUS (16; 16%) and NHL (4 marginal zone lymphoma, 1 CLL; 5%). The median age at cryoglobulin diagnosis was 66 years (range 39-90). There was a kappa light-chain predominance in the majority (85%). MYD88^L265Pwas present in 44/49 (90%) of WM and 3/8 (38%) MGUS cases. CXCR4 was mutated in 5/13 (38%) WM cases. Coexistent IgM-associated disorders were present in 25: cold agglutinin disease/syndrome (CAD/CAS, 15%), Bing-Neel syndrome (7%), anti-MAG antibodies (5%), Schnitzler syndrome (1%). Those with coexistent CAD/CAS had characteristics of a CAD clone, significantly associated with MGUS (vs WM/NHL, p<0.0001) and MYD88-wild type (p<0.0001). Patients with co-existent anti-MAG antibodies were significantly more likely to have MGUS (p=0.0245). Median M-protein at diagnosis of cryoglobulinaemia was 12g/l (range 0-63) and lowest in the MGUS cohort vs WM vs NHL (4g/l vs 16g/l vs 10g/l, p=0.0003). The majority were diagnosed with cryoglobulinaemia >3 months after diagnosis of the underlying IgM disorder (60/98; 61%), at a median of 46 months (range 4-442) and longer in those with WM compared with MGUS or NHL (51 vs 17 vs 13 months, p=0.023).

Forty nine percent were symptomatic at cryoglobulinaemia diagnosis, with a trend towards a greater proportion in those with MGUS/NHL vs WM (75%/60% vs 43%, p=0.0569). The most common symptoms were cutaneous/vasomotor symptoms (28%), neuropathy (21%), hyperviscosity (10%), arthralgia (7%) and renal involvement (2%). No cases had cardiac or pulmonary involvement.

At a median follow up of 2.4 years (range 0-9.4), 2-year overall survival (OS) was 89% (95% CI 80-94), 5-year OS was 73% (95% CI 56-84). Age was the only predictor of OS (Hazard ratio [HR] 1.07, 95% CI 1.01-1.12, p=0.006). Fourteen patients required chemoimmunotherapy for cryoglobulinaemia at a median of 1 month (0-7) from diagnosis for cutaneous manifestations (5/14; 36%), cryoglobulinaemic glomerulopathy (2/14; 14%) or hyperviscosity (9/14; 64%). Independent predictors of cryoglobulinaemia-indicated treatment-free survival/death included cutaneous involvement (HR 1.48, 95% CI 1.21-7.7.92, p=0.018) and hyperviscosity (HR 5.21 95% CI 4.21-27.8, p<0.0001) at cryoglobulinaemia diagnosis on multivariate analysis.

Conclusions: This is the largest reported series describing the characteristics of IgM-associated type I cryoglobulinaemia. It is common amongst patients with monoclonal IgM disorders and approximately half of patients may be symptomatic. Distinct clonal populations are present in which type I cryoglobulinaemia may develop including an MYD88^L265P WM clone and MYD88-wild type CAD/anti-MAG clone. Treatment may be required selectively in those with hyperviscosity, cutaneous or renal involvement, in a short time from diagnosis.

Rismani:Astra Zeneca: Honoraria, Speakers Bureau. Wechalekar:Janssen: Honoraria, Other: Travel Support; Attralus: Honoraria; Takeda: Other: Travel Support; Alexion: Honoraria, Other: Travel Support; GSK: Honoraria. Vos:Beigene: Research Funding; Sanofi: Consultancy; Celgene: Other: Travel support. D'Sa:Janssen; Sanofi; BeiGene: Consultancy; janssen; beigene: Other: grant funding .