Autoimmune Cytopenia Associated with Indolent B-Cell Clones: A Large Multicentric Cohort Study

Introduction

Autoimmune cytopenias (AIC) are a group of rare diseases sharing immune-induced accelerated destruction and/or impaired production of blood cells. AIC can be associated with overt B-cell lymphoid neoplasia. In that case, the management is based on the treatment of the hematological malignancy. However, AIC can be associated with indolent B-cell clones (IBC). In that case, the treatment of the AIC is not consensual. We aimed to describe the treatments used in France for IBC-associated AIC, and to compare their effectiveness, safety, and impact on IBC progression.

Methods

We conducted a multicenter, retrospective observational study including adults treated between 2000 and 2022 for a definite AIC (immune thrombocytopenia, ITP; autoimmune hemolytic anemia, AIHA; or Evans syndrome, ES) associated with an IBC, namely: chronic lymphocytic leukemia (CLL), marginal zone lymphoma (MZL), lymphoplasmacytic lymphoma, monoclonal B lymphocytosis, and mantle cell lymphoma. Patients who required a specific treatment of the underlying IBC for one or several of the following reason(s) were excluded: extensive marrow infiltration leading to impaired megacaryopoiesis and/or erythropoiesis, massive organ infiltration and/or compressive lymphadenopathies, lymphocytosis doubling within 6 months (with a lymphocytes count >30 x 10 ⁹/L), doubling of lymphadenopathy size within 2 months, hyperviscosity, and any other IBC-related condition requiring treatment (amyloidosis, neuropathy...).

Patients were classified according first-line treatment for AIC: group 1 for those treated without chemotherapy (corticosteroids, intravenous immunoglobulin, rituximab...); group 2 for those treated with chemotherapy (cyclophosphamide, ibrutinib...). Only the first-line treatment was assessed. Response to treatment was defined according to standard international criteria. An infection was defined as serious if graded >2, according to the Common Terminology Criteria for Adverse Events. The progression was defined as the need to urge lymphoma-specific therapy. Subgroup analyses were performed by type of AIC (ITP, warm/mixed AIHA, cold agglutinin disease, and ES). Overall survival was estimated using the Kaplan-Meier method and comparison was performed using Log-rank test.

Results

In total, 187 patients were included throughout 30 French university and general hospitals using the French reference center network for immune cytopenias in adults. The median age at diagnosis of AIC was 75 years (range 43 to 97 years) with a male/female ratio of 1.47 (Table 1). We observed 105 (56.1%) patients with AIHA, 80 (42.8%) with CLL and 44 (23.5%) with MZL. In most cases (58.8%), the time elapsed between IBC and AIC diagnosis was £6 months.

We included 132 (72.2%) patients in group 1. Among them, 75 (55.6%) patients were treated with only corticosteroids +/- intravenous immunoglobulin, 52 (38.5%) with rituximab, 2 with splenectomy, and 1 with dapsone. We included 52 (27.8%) patients in group 2. Among them, 46 (88.5%) patients were treated as first-line with a rituximab-cyclophosphamide-dexamethasone combined regimen, 2 with rituximab-bendamustine, 2 with chloraminophen, 1 with fludarabine-cyclophosphamide-dexamethasone, and 1 with ibrutinib.

Both overall response and relapse rates were similar between groups: 86.6% versus 86.5% and 45.5% versus 41.5%, respectively. We did not find any difference in subgroup analyses by type of AIC.

Serious infections were observed in 17.6% patients: 17.8% in group 1, 17.3% in group 2.

With a median of follow-up of 39.8 months (95% IC 30.0 to 51.3), the overall survival did not differ between group 1 (84.0% at 4 years, 95% IC 73.7 to 90.5) and group 2 (81.8% at 4 years, 95% IC 66.1 to 90.7), nor the progression rate of IBC was similar in both groups (9.6% and 7.7%, respectively).

Conclusion

We report the largest cohort of AIC associated with IBC. So far, very few patients with lymphomas such as MZL have been described in this situation. We observed that treatments were heterogeneous. Whatever the strategy used (treating AIC only or also using chemotherapy for the IBC), the effectiveness and safety profiles of first-line treatments were not different. Additional analyses are ongoing to better clarify the impact of rituximab alone versus rituximab and chemotherapy, and IBC' characteristics on the overall progression-free survival.