Case Study Management of Crystal Cryoglobulinemia in a Patient With Chronic Lymphocytic Leukemia

A 64-year-old man with a history of heart failure with preserved ejection fraction and hypertension presented with progressive dyspnea. Initial labs revealed worsening renal function, a serum creatinine level of 2.1 mg/dL (patient’s baseline: ~1.0 mg/dL), and pancytopenia (white blood cell count [WBC]: 3.3 K/uL, hemoglobin: 7.8 g/dL, platelets: 118 K/uL). He was also found to have an IgG kappa monoclonal gammopathy; quantification yielded 0.4 gm/dL (normal, 0 gm/dL), with a kappa light chain level of 16.96 mg/dL (normal, 0.33-1.94 mg/dL) and low serum total complement levels (CH50 <16; reference value: >41 U/mL). Urine studies revealed proteinuria and hematuria. An echocardiogram showed a newly reduced left ventricular ejection fraction of 20-25% (previously 50%).

During this hospitalization, the patient was noted to have worsening ischemia of his right foot (Figure 1) and left second and third digits. Ultrasound of the right lower extremity confirmed deep vein thrombosis in multiple veins. A computed tomography (CT) angiogram of the chest revealed a subacute pulmonary embolism.

Gangrene Foot

Figure 1: Marked gangrene (red) of the right foot

Renal biopsy specimens demonstrated a pattern of membranoproliferative glomerulonephritis injury, staining positive for IgG and kappa on light microscopy. Ultrastructurally, electron-dense deposits exhibited lattice-like structures and crystal formation (Figure 2). Together, these findings were suggestive of IgG kappa crystal cryoglobulinemic glomerulonephritis type 1 with monoclonal gammopathy of renal significance (MGRS).


Crystal Formation

Figure 2: Electron microscopy image depicting intraluminal electron-dense deposits in rod and rectangular shapes, consistent with crystal formation.

Additional serological evaluation revealed a positive serum cryoglobulin of 5% (reference value: 0%). Peripheral blood flow cytometry demonstrated a kappa-restricted monoclonal B-cell population expressing CD19, CD5, and CD38 but negative for CD10, raising the concern of chronic lymphocytic leukemia (CLL). Bone marrow biopsy confirmed mature B-cell lymphoma with a CLL phenotype comprising 30% of marrow cellularity. The diagnosis of type 1 crystal cryoglobulinemia secondary to IgG kappa monoclonal gammopathy in the context of underlying CLL was made.

What treatment strategy should initially be considered to prevent further vascular complications?

  • A. High-dose steroids only
  • B. Clone-directed therapy
  • C. Plasmapheresis +/- hemodialysis
  • D. Aspirin

Answer: C

Crystal cryoglobulinemia (CCG), a rare variant of type I cryoglobulinemia, is classically associated with an underlying monoclonal gammopathy. Crystal cryoglobulins are created when immunoglobulins spontaneously self-assemble into extracellular crystal arrays. The deposition of crystallized paraproteins within vessels induces severe systemic hypoperfusion and an occlusive vasculopathy that culminates in multi-organ failure. Most commonly, the resultant ischemia manifests as cutaneous lesions and renal vasculopathy, which can progress to fulminant kidney failure requiring renal replacement therapy. CCG is associated with lymphoproliferative disorders such as multiple myeloma and Waldenstrom macroglobulinemia but is rarely seen in CLL, though it often confers a poor prognosis. Given its high morbidity and mortality, timely and adequate treatment is necessary to prevent further vaso-occlusive complications.

Management of Crystal Cryoglobulinemia in a Patient with Chronic Lymphocytic Leukemia

The management of CCG ultimately depends on the underlying cause. However, most therapies reflect one of two aims:

  1. Reducing the level of monoclonal immunoglobulins in the blood
  2. Targeted treatment of the underlying source of paraproteinemia

Serum levels of crystallized immunoglobulins (#1) can be reduced via plasma exchange with or without anticoagulation. Plasmapheresis is an effective, albeit temporary, treatment method indicated in patients with acute systemic vasculopathy. Our patient received 10 sessions of plasmapheresis and one session of hemodialysis in addition to heparin and high-dose Prednisone without further vascular complications.

What About Definitive Treatment?

Definitive treatment of CCG secondary to a lymphoproliferative disorder involves directly targeting B-cell clonal proliferation to reduce the source of immunoglobulin production (#2). In our case, this was accomplished via acalabrutinib therapy. Correspondingly, the most effective treatment of MGRS-related kidney diseases also aims to suppressing clonal proliferation via clone-directed therapies. Treatment is often mandatory and sometimes urgent to prevent renal deterioration and progression to end-stage renal disease (ESRD). Recovery of renal function is possible with adequate hematologic response, which occurred in our case.

In summary, this case of type I CCG with MGRS was driven by an underlying lymphoproliferative disorder, CLL. Prompt temporizing reduction of circulating IgG with plasmapheresis and definitive therapy for CLL resulted in a good outcome for the patient. Patients diagnosed with CCG should be evaluated for an underlying lymphoproliferative disorder to rapidly initiate both temporizing and definitive therapy.

References

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7. Papo T, Musset L, Bardin T, et al. Cryocrystalglobulinemia as a cause of systemic vasculopathy and widespread erosive arthropathy. Arthritis Rheum. 1996;39(2):335-340.

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9. Wee C, Lim J, Lee J. Cryocrystalglobulinemia-An Uncommon cutaneous presentation of multiple myeloma and novel finding of transepidermal elimination of crystals. Am J Dermatopathol. 2021;43(12):e241-e244.

Acknowledgement: This article was edited by Kaitlyn Dykes, MD, and Urshila Durani, MD, MPH. Drs. Dunton and Jain indicated no relevant conflicts of interest.