Clinical significance of dynamic changes in platelet satellitism during multiple myeloma therapy Free

Background: Platelet satellitism (PS) is a rare form of pseudothrombocytopenia characterized by rosette-like clusters of platelets surrounding neutrophils. This phenomenon occurs due to autoantibodies targeting platelet glycoprotein IIb/IIIa in the presence of EDTA, which promotes the binding of platelets to neutrophils via the Fcγ receptor (CD16) on neutrophils. PS has an occurrence rate of approximately 0.008% and is often associated with autoimmune diseases, B-cell malignancies, and infections. We observed a case of PS during the treatment of multiple myeloma (MM), where PS became apparent, disappeared, and then reemerged during MM therapy. Our laboratory investigations indicated a causal relationship with lenalidomide.

Case Presentation: A male in his 70s was referred to our hematology department for evaluation of anemia and the presence of circulating myelocytes. A bone marrow biopsy revealed 18.4% clonal plasma cells, leading to a diagnosis of IgA-κ type multiple myeloma, classified as stage II according to the Revised International Staging System. There were no high-risk cytogenetic abnormalities, and there was no evidence of concomitant amyloidosis or lytic bone lesions.

The patient achieved a complete response after three cycles of bortezomib, lenalidomide, and dexamethasone (VRd) therapy. During the administration of G-CSF prior to autologous peripheral blood stem cell harvesting, we observed progressive thrombocytopenia despite the absence of concurrent chemotherapy. Peripheral blood smears revealed PS. This phenomenon resolved following stem cell transplantation but re-emerged during maintenance therapy with lenalidomide.

Methods and Results: The level of PS was assessed semi-quantitatively through manual counting using microscopy and scattergram analysis in the white blood cell and nucleated red blood cell (WNR) channel, whenever feasible. PS was exclusively observed in samples anticoagulated with EDTA. When peripheral blood samples exhibiting PS were kept at room temperature for six hours, we noted that neutrophils engulfed the platelets.

PS was quantified over the course of the patient's treatment. The median number of platelets adhering to each platelet at various time points was as follows: 0 (baseline), 4.1 (post-VRd therapy), 5.1 (two days after the initiation of G-CSF), 0 (post-autologous transplantation), and 3.3 (after the start of lenalidomide maintenance). Notably, during VRd therapy and early G-CSF administration, scattergrams displayed abnormal clustering in the neutrophil region.

The patient's plasma induced PS when added to blood cells from healthy donors, but not in cells from a myelodysplastic syndrome patient with agranulated platelets. This suggests that intact platelet granules are necessary for the process.

To confirm the role of CD16 expression, flow cytometry was performed to measure the mean fluorescence intensity (MFI) of CD16. Following the administration of G-CSF, an initial increase in mature neutrophils was observed, indicated by a higher shift in CD16 MFI, which correlated with rising PS levels. Then, as the number of immature neutrophils increased over time, represented by a decrease in CD16 MFI, there was a corresponding decrease in PS levels. These findings suggest that the maturation status of neutrophils affects the level of PS.

During lenalidomide maintenance therapy, PS occurred again without significant changes in CD16 MFI.To evaluate the direct effect of lenalidomide, we incubated plasma from a donor patient undergoing lenalidomide treatment with the case plasma to assess its impact on PS levels. The resulting mixed plasma, which likely contained a higher concentration of lenalidomide, did not alter the PS levels. This indicates that lenalidomide may promote PS by enhancing the production of autoantibodies rather than through a hapten-based mechanism.

Discussion and Conclusion: This unusual case of PS appeared to occur following the administration of lenalidomide. G-CSF may exacerbate PS by increasing the expression of CD16 on neutrophils. This case highlights the potential necessity of monitoring for PS when thrombocytopenia occurs during lenalidomide treatment, especially with G-CSF support.