Daratumumab for disabling cold agglutinin disease refractory to B‐cell directed therapy
Authors: Oliver Tomkins, Sigbjørn Berentsen, Suzanne Arulogun, Mallika Sekhar, Shirley D'Sa
Journal: American Journal of Hematology (2020)

To the Editor: Cold agglutinin disease (CAD) is a form of autoimmune hemolytic anemia, mediated by the classical complement pathway. Cold agglutinins (CA) are autoantibodies, usually of the IgMκ class, which target the I antigen on erythrocyte surface at 4°C, but may also react at temperatures approaching 37°C.1 An IgMκ gammopathy is typically identified, and a distinct underlying lymphoproliferative disorder (LPD) is recognized, which may be indistinguishable from lymphoplasmacytic lymphoma (LPL).2-4 Bone marrow examination usually shows intraparenchymal nodules with small CD20+, CD38−, CD5+/− IgMκ+ monoclonal B-cells and surrounding monoclonal IgM+,κ + plasma cells.4 A subpopulation of clonal, long-lived chemoimmunotherapy-resistant plasma cells is assumed to exist.1, 5 Therapy has been directed at the underlying clone by using rituximab, often in combination with bendamustine, fludarabine, or bortezomib.3 Upstream complement inhibition is an emerging therapy, but circulatory symptoms are not complement-mediated and persist.3 Cold-induced, agglutination-mediated, circulatory symptoms are recorded in 40%-90% of patients.1, 2 We present a Caucasian male, aged 48, who was diagnosed with CAD in 2011. At the outset, the hemolysis was well-compensated (Figures 1 and 2), with a presence of an IgM CA, and direct antiglobulin test strongly positive for C3d, with CA titre 1024 at 2°C-8°C. Serum immunofixation was negative for a monoclonal immunoglobulin. Free κ light chains were 172 mg/L, with a κ:λ ratio of 17.5. Autoantibody screen was negative, and cryoglobulins were not detected. Bone marrow aspirate and trephine showed no clonal B-cells, and CT imaging was normal. His symptoms were dominated by painful and disabling acrocyanosis, worsened by cold exposure, and led to early retirement as an aeronautical engineer. Sequential treatments were trialed, with minimal symptomatic response, including rituximab monotherapy and rituximab with prednisolone. Therapeutic plasmapheresis failed due to agglutination in the equipment despite active warming. Single-agent bortezomib required discontinuation after paradoxical worsening of symptoms with intense acrocyanosis. Repeat bone marrow biopsy in April 2015 revealed a CD138+ lymphoplasmacytic infiltrate affecting 20% of the intertrabecular surface, with scattered B-cells and κ-restricted plasma cells, but immunofixation remained negative. Circulatory symptoms continued to dominate and the patient became anemic, with hemoglobin 116 g/L, LDH 1611 U/L and bilirubin 30 μmol/L. Bortezomib-cyclophosphamide-prednisolone was consequently used to address the lymphoid/plasma cell clone, with only transient symptomatic improvement and rise in hemoglobin to 131 g/L. Treatment was curtailed after five cycles due to loss of clinical response and onset of neuropathy. A year later, bone marrow examination demonstrated a cyclin D1+ plasma cell dyscrasia, a proportion of which expressed IgM, and sparse small lymphocytes. A MYD88 L265P mutation was newly identified. Two faint IgMκ monoclonal components were newly detected, and the free κ:λ ratio was 75. Lenalidomide and dexamethasone, followed by cyclophosphamide and prednisolone, achieved no clinical response, and the patient remained markedly impaired, unable to work, and significantly restricted in daily activities. Even tepid beverages caused oropharyngeal pain and nausea. Cold weather also caused troublesome upper respiratory tract discomfort. A repeat bone marrow examination demonstrated 10% disease infiltration, predominantly with CD138+ plasmacytic differentiation. We elected to commence treatment with 16 mg/kg of daratumumab weekly for weeks 1-8, two-weekly for weeks 9-24, and every 4 weeks thereafter. Within the first 2 weeks, he noticed significant improvement in his acrocyanosis and was able to enjoy previously prohibited activities. His hemoglobin increased from 125 to 166 g/L by week 8 on therapy, with simultaneous normalization of LDH and haptoglobin (Figure 1). A significant increase in hemoglobin was seen within two doses of daratumumab, with normalization in LDH and haptoglobin. A reduction in serum IgM and the CA titre is evident. The CA titre at 2°C-8°C improved from 1024 to 256, and at 30°C from 64 to 4. Repeat bone marrow trephine examination demonstrated a residual infiltrate; however, there were now only scattered CD138+ plasma cells alongside a slight re-emergence of CD20+ B-lymphocytes. This is the first report of successful treatment with daratumumab in CAD. The patient's bone marrow LPD was consistent with the specific picture designated as "CAD-associated LPD" by histomorphology, although this LPD is usually negative for the MYD88 L265P mutation.4 In a proportion of patients with otherwise-typical primary CAD, however, the bone marrow histology will be described as LPL, and some of these cases are MYD88 L265P positive.2 The recent international AIHA consensus document states, "We recognize that occasional patients in whom the bone marrow histology has been interpreted as other low-grade LPDs, such as LPL, should also be classified as having primary CAD."3 Therefore, we consider our patient as having primary CAD rather than a secondary cold agglutinin syndrome. Our patient's presentation was dominated by life-changing agglutination-mediated ischemic symptoms with compensated hemolysis, a phenotype seen in 10% of patients with CAD.2 The plasmacytic differentiation and cyclinD1 expression highlight the potential of clonal development, and are likely explained by selection of long-lived plasma cells resistant to B-lymphocyte depleting therapies.1, 5 In our patient, the data do not allow a firm conclusion on this mechanism, but are consistent with such development, providing the most likely explanation for the resistance to B-cell directed therapy and dramatic effect of daratumumab. Although the discrepancy between the significant effect of daratumumab and resistance to bortezomib cannot readily be mechanistically explained, it is well-known that bortezomib monotherapy is effective in less than half of patients with CAD.3 It is unlikely that removal of CD38 expressed on erythrocytes following administration of daratumumab is responsible, as this should not also result in the marked decline in CA titre and IgM levels observed. Although not proven, one might speculate whether the previous B-cell directed therapies might have been necessary for the dramatic favorable effect of specific plasma cell directed therapy. This is the first description of the use of daratumumab in CAD. The rapid and marked clinical and biochemical response was striking and highly meaningful to the patient, who is now seeking to return to work. Further work is required to fully establish the mechanism of action, but, if confirmed, our observation has the potential to provide a novel and attractive approach for cases of CAD with disabling, non-complement mediated symptoms of CAD refractory to B-cell directed therapies. Shirley D'Sa has received honoraria and research grant funding for other projects by Janssen-Cilag Ltd. There are no other conflicts of interest.