Table 1.

International Definition of iMCD-TAFRO

1. Definite iMCD-TAFRO Criteria

1.1 Clinical Criteria (all 4 required)

➢ Thrombocytopenia (T): Pre-treatment nadir platelet level ≤ 10 x 104/μL

➢ Anasarca (A): Pleural effusion, ascites, or subcutaneous edema with CT scan

➢ Fever or hyperinflammatory status (F): Fever ≥ 37.5°C of unknown etiology or CRP ≥ 2.0 mg/dL

➢ Organomegaly (O): Small volume lymphadenopathy in two or more regions, hepatomegaly, or splenomegaly on CT scan

1.2 Pathological Criteria (required)

➢ Lymph node consistent with iMCD: Must be consistent with histopathologic features of the International iMCD Diagnostic Criteria†

In brief, atrophic germinal centers, concentric rings of mantle zone cells, and interfollicular hypervascularization or plasmacytosis. Negative for light chain restriction and HHV-8.

1.3 Additional Clinical and Pathological Criteria (at least 1 of the following required)

➢ Renal insufficiency (R): Pre-treatment eGFR ≤ 60 mL/min/1.73 m2 , creatinine >1/1 mg/dL (female)/ >1.3 mg/dL (male), or renal failure necessitating hemodialysis.

➢ TAFRO-consistent bone marrow: Reticulin fibrosis (R) or megakaryocytic hyperplasia, without evidence of an alternative diagnosis

1.4 Exclusion Criteria (required): see below

1.5 Supportive Clinical Criteria (not required but strongly supportive)

➢ Renal insufficiency (R): Pre-treatment eGFR ≤ 60 mL/min/1.73 m2 , creatinine >1/1 mg/dL (female)/ >1.3 mg/dL (male), or renal failure necessitating hemodialysis.

➢ TAFRO-consistent bone marrow: Reticulin fibrosis (R) or megakaryocytic hyperplasia, without evidence of an alternative diagnosis

➢ Absence of polyclonal hypergammaglobulinemia (immunoglobulin G ≤ 1.2x upper limit of normal by nephelometry

➢ Elevated alkaline phosphatase with mild to no elevation in bilirubin and transaminases

2. Probable iMCD-TAFRO Criteria: All 4 Clinical Criteria and Additional Clinical and Pathological Criteria met, but Pathological Criteria not able to be assessed because no lymph node biopsy was performed or an insufficient specimen was obtained

3. TAFRO syndrome, not iMCD-TAFRO: All 4 Clinical Criteria and Renal insufficiency (R) met, but lymph node biopsy was not consistent with iMCD OR an exclusion criteria diagnosis was made

Exclusion Criteria - Must rule out the following diseases

➢ Infectious diseases - including the below but not limited to:

1. HHV-8

2. EBV-associated lymphoproliferative disorders

3. Acute HIV infection

4. Tuberculosis

5. COVID-19 cytokine storm syndrome

➢ Autoimmune/rheumatologic diseases:

1. Systemic lupus erythematosus

2. Sjögren syndrome

3. Rheumatoid arthritis

4. Adult-onset Still disease

5. Juvenile idiopathic arthritis

6. IgG ≥ 3,400 mg/dL (suggestive of autoimmune diseases or plasma cell dyscrasias)

7. Primary hemophagocytic lymphohistiocytosis

➢ Malignancy - including the below but not limited to:

1. Malignant lymphoma

2. Multiple myeloma

3. Metastatic cancer

4. POEMS syndrome

Abbreviations: CRP, C-reactive protein; CT, computed tomography; eGFR, estimated glomerular filtration rate; HHV-8, human herpesvirus-8.

^†International, evidence-based consensus diagnostic criteria for HHV-8–negative/idiopathic multicentric Castleman disease. Blood. 2017 Mar 23;129(12):1646-1657.