Phase II Trial of Zanubrutinib in Primary Cold Agglutinin Disease. CaZa Study
Cold agglutinin disease (CAD) is defined as a chronic autoimmune hemolytic anemia (AIHA) with a monospecific direct antiglobulin test (DAT) strongly positive for C3d and the presence of cold agglutinins (CA; titer ≥ 64 at 4°C). Patients may have a B-cell clonal lymphoproliferative disorder (LPD) detectable in blood or marrow but no clinical or radiological evidence of malignancy. CAD can lead to AIHA, peripheral ischemic symptoms (cold-induced peripheral symptoms such as acrocyanosis etc.), or both. The CAs are typically monoclonal IgM antibodies produced by the clonal B-cells, usually IgM kappa with specificity for the I antigen on erythrocytes. There is no curative treatment. Current treatment options include rituximab monotherapy, however this has only a limited and short-lasting effect. Rituximab in combination with chemotherapy induces deeper and more durable responses, however since CAD patients typically do not have an overt malignancy this comes with concerns about short- and long-term toxicity. Novel complement inhibitors may be effective for the hemolysis but are not expected to be effective against cold induced peripheral symptoms while this is directly IgM mediated. Bruton Tyrosine Kinase inhibitors (BTKis) are effective in many B-cell lymphoproliferative disorders including the IgM producing clone of Waldenström macroglobulinemia (WM) and were very effective on both AIHA and peripheral ischemic symptoms in patients with CAD based on retrospective data.
⁃ In order to be eligible to participate in this study, a patient must meet all of the following criteria:
⁃ CAD diagnosis defined by the combination of:
• Chronic hemolysis (\>3 months; suppressed haptoglobin) and
• Cold agglutinin titer of 64 or higher at 4°C and
• Positive direct antiglobulin test, strongly positive (at least 2+) with anti-C3d and negative or weakly positive (maximum 2+) with anti-IgG,
⁃ AND:
⁃ The presence of a clonal B-cell lymphoproliferative disorder defined by:
• M-protein by serum electrophoresis confirmed by immunofixation, and/or
• A clonal CD20 positive lymphocyte population in the bone marrow (a very small clone visible only by flow cytometry is allowed)
⁃ Indication for therapy:
⁃ Hb ≤ 10.5 g/dL
⁃ AND/OR
⁃ Considerable CIPS (grade 2 or more; see appendix E)
⁃ Relapsed or refractory after at least one prior CAD treatment, OR is treatment naïve and not eligible for currently available treatment options, per clinician's judgement.
⁃ Age ≥ 18 years.
⁃ ECOG/WHO performance status ≤ 2 (see appendix B). WHO performance status 3 is allowed if related to the CAD.
⁃ Adequate bone marrow function as defined by:
⁃ Absolute neutrophil count (ANC) \> 1.0 × 109/L, and
⁃ Platelets ≥ 100 x109/L.
⁃ Ferritin levels above the lower limit of normal (LLN). Concurrent treatment with iron supplementation is permitted if the patient has been on a stable dose during the previous 4 weeks.
⁃ Total bilirubin level above the upper limit of normal (ULN), as a measurable parameter for hemolysis, and that is not attributable to Gilbert's syndrome.
⁃ Negative pregnancy test at study entry for woman of childbearing potential.
⁃ Women of childbearing potential must be: (1) surgically sterile or ≥ 2 years after the onset of menopause; (2) willing to use a highly effective contraceptive method such as oral contraceptives, intrauterine device, or sexual abstinence during study treatment and for ≥ 90 days after last dose of zanubrutinib.
⁃ Male patients with a female partner of childbearing potential are eligible if vasectomized or if they agree to the use of barrier contraception with other methods as described above during the study treatment period and for ≥ 90 days after the last dose of zanubrutinib.
⁃ Written informed consent.
⁃ Patient is capable of giving informed consent and can understand and agrees to comply with the requirements of the study and the schedule.