Acrocyanosis revealing chronic lymphocytic leukemia.

Cold agglutinin disease arising in the context of chronic lymphocytic leukemia can misdiagnose a warm autoimmune hemolytic anemia.

Report

A 61‐year‐old man was referred in December (cold winter season in the east area from France) for assessment of fatigue and a bronchitis that had been dragging on for 3 weeks. The physical examination revealed acrocyanosis but neither lymphadenopathy nor hepatosplenomegaly. Laboratory findings were: hemoglobin 7.9 g/dL, mean cell volume 91 fL, leukocytes 17.770 × 109/L, platelets 546 × 109/L.

The blood differential demonstrated 57% (10.129 × 109/L) lymphoïd cells (21% of which showing nuclear clefts; Fig. 1B). The immunophenotype pointed out monoclonal B‐cells expressing dimly surface IgM κ light chains. The lymphoid cells co‐expressed CD19 and CD5 markers, and were CD20 (weak), CD22/CD79b (weak), CD23, CD24, CD43, CD38, CD200 (high), and FMC7 (weak) positive. CD10, CD11c, CD25, and CD103 were negative. ZAP‐70 detection was not performed. Serum electrophoresis and immunofixation showed hypogammaglobulinemia and a M‐component at 5.8 g/L. The karyotype was 46, XY, +12. Molecular analysis of immunoglobulin variable heavy chains (IGVH) found nonmutated B‐cells. The retained diagnosis was chronic lymphocytic leukemia (CLL), Matutes score 4 1, with trisomy 12.

Figure 1

Clumped erythrocytes (A) along with abnormal lymphoïd cells (B). Peripheral blood film, MGG ×200 and ×500.

Unexpectedly, the peripheral blood smear observation also showed red blood cells with moderate anisocytosis, some spherocytes, polychromatophilia, and mainly, numerous clumped erythrocytes (Fig. 1A). Investigations confirmed a mild hemolytic anemia (direct bilirubin 41 μmol/L, LacticoDesHydrogenase 460 U/L, haptoglobin below the level of detection). The direct antiglobulin test (DAT) was positive for C3d only (negative for anti‐IgG). A high titer of 4.096 at 4°C agglutinin with anti‐I specificity was affirmed. The thermal amplitude testing at 30°C (with and without albumine) was positive. A cold agglutinin disease (CAD) was evoked.

No blood cell transfusion was performed. The patient responded poorly to the prevention of cold exposure, but improved after the administration of high‐dose prednisolone (80 mg daily). The treatment was tapered after 3 weeks, when partial response was achieved (improvement of clinical symptoms, Hb 10.5 g/dL, IgM 3.6 g/L). Unfortunately, the patient was then lost of sight.

A clinical condition not commonly seen in CLL is reported here. Autoimmune disorders may precede or follow the diagnosis of CLL 2. In our case, the cold agglutinin and the increased lymphocytes were discovered at the time of the diagnosis. The association of CAD and CLL is a scarce finding. The autoantigens usually belongs to the I/i system 3, 4. Since the B cells of our case were not somatically mutated, one might speculate that the cold agglutinin might not be a paraprotein synthesized by the neoplastic clone, but an other IgM Kappa which is not sharing the same idiotype as expressed on the clonal B‐cells. Nevertheless, IgM antibodies can be produced without somatic IGVH hypermutation and our speculation remains unproved. Although patients with CAD typically have cold agglutinin with high titer at 4°C, not all patients with high titer cold agglutinin have CAD and the thermal amplitude of the cold agglutinin is a critical result. The cold antibody may be pathogenic if it reacts at 30°C or above, and a CAD can then be affirmed 5. Steroids are not usually effective in CAD and successful avoidance of cold is the first‐line therapy. Though unspecific, our patient's response to treatment (poor with prevention of cold exposure but partial response after steroids) could had better matched with the diagnosis of a warm autoimmune hemolytic anemia (AIHA) 6. But, in that hypothesis, the only DAT positivitv for C3d would had unfitted the picture of a warm antibody AIHA. A super Coombs investigation could have helped for classification but had not been performed in our case. Only a minority of CLL patients harboring a positive DAT test will develop AIHA 7. Though a few patients with warm AIHA have been found to present with positive DATs with anti‐C3d only, the CAD diagnosis was affirmed in our case by the thermal amplitude of the antibody.

Conflict of Interest

None declared.