Obinutuzumab Rescue in Rituximab Resistant Mixed Cryoglobulinemia
Bibliographic record
Abstract
We previously reported a persistent mixed cryoglobulinemic membranoproliferative glomerulonephritis secondary to a monoclonal gammopathy of renal significance despite hepatitis C eradication.1Pelletier K. et al.Persistent mixed cryoglobulinemia despite successful treatment of hepatitis C, aggressive B-cell-directed therapies, and long-term plasma exchanges.Kidney Int Rep. 2019; 4: 1194-1198Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar While initially responsive to rituximab, the patient became refractory to it, and subsequently failed cyclophosphamide, bortezomib and bendamustine. Azathioprine proved partially efficacious as demonstrated by a relapse within a month of its cessation in order to administer bendamustine. He remained dependent on weekly plasmapheresis. To improve disease control, obinutuzumab was added to azathioprine. Four doses of 1 g were given every 3 weeks, followed by 3 additional doses every 8 weeks. This translated into lasting reductions in proteinuria, rheumatoid factor and serum free light chain ratio (Figure 1). Plasmapheresis requirements decreased, and azathioprine and prednisone doses were tapered. At 1-year post obinutuzumab therapy, CD19+/CD20+ lymphocytes remain undetectable. No opportunistic infection occurred. Obinutuzumab is a novel humanized type II anti-CD20 monoclonal antibody with superior B-cell depleting capabilities, mediated by enhanced direct cell death via complement activation and antibody-dependent phagocytosis.2Freeman C.L. Sehn L.H. A tale of two antibodies: obinutuzumab versus rituximab.Br J Haematol. 2018; 182: 29-45Crossref PubMed Scopus (37) Google Scholar Although only approved for the treatment of hematological malignancies, it is being investigated in lupus nephritis and membranous nephropathy. A case of chronic lymphoid leukemia related immune-complex mediated membranoproliferative glomerulonephritis was successfully treated with it.3Jain P. et al.Membranoproliferative glomerulonephritis and acute renal failure in a patient with chronic lymphocytic leukemia: Response to obinutuzumab.Hematol Oncol Stem Cell Ther. 2017; 10: 151-154Crossref PubMed Scopus (3) Google Scholar To our knowledge, this is the first report of a response to obinutuzumab in refractory monoclonal gammopathy of renal significance. It reduced the production of pathogenic monoclonal RF permitting the weaning of concomitant therapies. Rescue therapy with obinutuzumab, or other new B-cell depleting therapies, should be considered in glomerular diseases where rituximab is indicated but has failed. Persistent Mixed Cryoglobulinemia Despite Successful Treatment of Hepatitis C, Aggressive B-Cell–Directed Therapies, and Long-term Plasma ExchangesKidney International ReportsVol. 4Issue 8PreviewCryoglobulins are Igs that precipitate in cold temperature. Three subsets have been described: type I consists of only monoclonal Ig, usually due to monoclonal gammopathy of undetermined significance, multiple myeloma, Waldenström macroglobulinemia, or chronic lymphocytic leukemia.1 Type II cryoglobulins contain polyclonal IgG and a monoclonal IgM with rheumatoid factor (RF) activity directed against the IgG, whereas type III contains both polyclonal IgG and IgM RF.2 Types II and III, also called mixed cryoglobulinemia, result in most cases from a B-cell proliferative process in the setting of persistent immune activation triggered by chronic hepatitis C virus (HCV) infection. Full-Text PDF Open Access
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.008 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".