Expression of SLAMF7 on hairy cell leukemia indicates therapy option with SLAMF7-antibody Elotuzumab

To the editor,

Hairy cell leukemia (HCL) is a rare, chronic B-cell lymphoproliferative disorder characterized by “hairy” B-lymphocytes in the bone marrow, spleen and sometimes extramedullary tissue [1]. The disease occurs four times more often in men than in women, and women respond better to therapy than men [2]. Most commonly, the clinical presentation includes pancytopenia with an increased risk for infection and splenomegaly. Extramedullary involvement may occur [3].

The diagnosis of HCL is based on peripheral blood flow cytometry and bone marrow biopsy for histology and immunohistochemistry. In flow cytometry, HCL cells express mature B-lymphoid cell antigens such as CD19, CD20, CD22, CD200. They are typically positive for CD11c, CD103, CD123 and CD25, while usually negative or dim for CD5, CD23, CD10, CD79b and CD27. This immunophenotypic pattern is widely used to discriminate classic HCL from the morphologically similar HCL variant (usually CD103+ but CD25-) and splenic marginal zone lymphoma (usually CD103- and CD11c-) [3]. The BRAF-V600E mutation is characteristic of HCL and should be determined by PCR. The mutation induces the RAF-MEK-ERK pathway, leading to cell proliferation [4].

At the time of diagnosis, 90% of patients have an indication for treatment, mostly due to pancytopenia. The cornerstones of HCL therapy are the purine nucleoside analogs Cladribine and Pentostatin. Recently, Rituximab has been added to first line therapy, either concurrently or sequentially to purine nucleoside analogs, achieving a deeper and more prolonged complete remission [1]. In case of contraindication to purine nucleoside analogs, interferon-alpha has been successfully utilized to improve peripheral blood counts [5]. Considering the characteristic BRAF-V600E mutation, the BRAF inhibitor Vemurafenib is also an option as targeted therapy [6]. The treatment of relapsed HCL includes MEK inhibitors, the BTK inhibitor Ibrutinib and a combination of Bendamustin and CD-20 antibodies [1]. Allogenic hematopoietic stem cell transplantation has been shown to be a therapeutic option for heavily pretreated patients [7].

Signaling Lymphocytic Activation Molecule (SLAM) family receptors are expressed in hematopoietic cells and play a crucial role in normal immune regulation [8,9]. As part of the SLAM receptor family, the Signaling Lymphocyte Activation Molecule 7 Family Member (SLAMF7) is known to be expressed on Natural Killer (NK) cells and plays a role in the regulation of B-lymphocyte proliferation [10]. Recently, we reported that SLAMF7 is expressed, besides in multiple myeloma, also in patients with NK/T cell lymphoma, patients with systemic mastocytosis and patients with NK-LGL or T-LGL [9]. Moreover, no expression is found on normal tissues or stem cells [[10], [11], [12], [13], [14]]. The physiological function of SLAMF7 on plasma cells and NK/T cells or NK-LGL or T-LGL cells is widely unknown. However, SLAMF7 inhibits production of proinflammatory cytokines by activated monocytes. Recently, Chen and coworker showed that SLAMF7 is critical for phagocytosis of haematopoietic tumor cells via Mac-1 integrin, which plays an important role in cancer control [11]. In Multiple Myeloma, SLAMF7 is already used as a therapeutic target for Elotuzumab, a humanized IgG1 monoclonal antibody. Elotuzumab tags the target cells for recognition by NK cells and activates the NK cells themselves by binding to SLAMF7 on their cell surface [9]. In this paper, we show for the first time that HCL cells have a strong expression of SLAMF7, which could be used as therapeutic approach.

We analyzed eight patients (6 male and 2 female) with HCL with a median age of 68 years (range 42-83 years). The diagnosis was made through flow cytometry of peripheral blood and bone marrow biopsy for immunohistochemistry. In flow cytometry, we defined cells co-expressing CD19 and CD103 as hairy cells. BRAF V600E gene was tested for mutation in five patients for further confirmation. We assessed the association between HCL and SLAMF7 by measuring the expression of SLAMF7 in CD19/CD103 positive cells with flow cytometry (Fig. 1). We defined an expression of SLAMF7 as positive if we detected SLAMF7 expression in at least 10% of the hairy cells within a given sample. All 8 patients were SLAMF7 positive. The median expression of CD19/CD103 in the peripheral blood flow cytometry of the 8 patients was 21,8%. BRAF V600E mutation was detected in 4 out of 5 patients (80%). In bone marrow samples we detected in 83% of all lymphocytes (mean) CD19/CD103 expressing hairy cells. Remarkably, 73,6% of these hairy cells expressed SLAMF7, with an expression range from 50% to 90,5% (Table 1). The bone marrow biopsy was stained with immunohistochemistry (IHC) for SLAMF7 (Fig. 1). IHC confirmed the strong expression of SLAMF7 on HCL.

Fig. 1.

Bone marrow biopsy showing the hairy cells with abundant cytoplasma and hairy projections. (arrow). SLAMF7 IHC staining.

Table 1.

Flow cytometry result in one of the study patients showing 73,6% SLAMF7 positivity among the CD19/ CD103 positive cells.

Here, 7 out of 8 patients (87,5%) developed symptoms of HCL and hence had to be treated. 5 out of 7 treated patients (71,4%) received the purine analog cladribine as a first line therapy, one treated patient received the anti-CD20 monoclonal antibody rituximab as a single-agent and another treated patient received cladribine combined with rituximab. The therapy decision was based on symptoms severity, blood count, age and ECOG performance status. Response assessment included a complete physical examination, including an evaluation of spleen size, complete blood count with differential and peripheral blood flow cytometry. A bone marrow biopsy to assess response was not done on a routine basis. All treated patients showed a significant response with a near normalization of peripheral blood counts, clinical regress of the splenomegaly and a decrease of CD19/CD103 positive cells to less than 5% of all examined cells in the peripheral blood flow cytometry.

In 2 out of 7 treated patients (28,5%) relapse was diagnosed. Relapse in both patients occurred 7-8 years after first line therapy with cladribine. Both relapsed patients (100%) received cladribine and showed a decrease of CD19/CD103 positive cells to less than 5% of all examined cells in the peripheral blood flow cytometry. Other known therapy options in relapsed patients with HCL include the purine analog Pentostatin, the anti BRAF monoclonal antibodies vemurafenib and dabrafenib, Bendamustine plus rituximab and single-agent rituximab.

The high expression of SLAMF7 indicates a new approach for targeted antibody therapy with the SLAMF7-antibody Elotuzumab in HCL. Elotuzumab is already in use for relapsed or refractory Multiple Myeloma in combination with Lenalidomide. The most common adverse events of the therapy regime are fatigue, lymphocytopenia and neutropenia leading to an increased risk of infections [11]. In a case of advanced systemic mastocytosis with a high SLAMF7 expression, Elotuzumab, in combination with Lenalidomide, was used as a part of induction therapy before allogenic stem cell transplantation, achieving almost a complete remission before transplantation [13].

Even though HCL responds very well to therapy with purine analogs, and other therapy options like BRAF inhibitors are already in use for relapsed HCL, most patients experience recurrence of the disease, requiring multiple treatments [14]. As demonstrated above, Chiara et al. even treated heavily pretreated or refractory HCL patients with allogenic hematopoietic stem cell transplantation [7]. Especially, the HCL variant is more resistant to chemotherapy. Therefore, more treatment options are needed for the management of relapsed classic HCL and HCL variant. In this article we present for the first time data that the SLAMF7-targeting antibody Elotuzumab, in combination with Lenalidomide and Dexamethasone, could be an option for the therapy of relapsed or refractory HCL with a strong expression of SLAMF7 on their cell surface.

Financial disclosure

The authors have nothing to disclose.

CRediT authorship contribution statement

Anju Singh: Resources, Data curation. Mathis Bittermann: Writing – review & editing, Formal analysis. Ibrahim Hammada: Writing – review & editing, Methodology. Simon Weisemann: Writing – review & editing, Validation. Mathias Vierbuchen: Writing – review & editing, Resources, Methodology, Investigation. Ahmet H. Elmaagacli: Writing – original draft, Resources, Formal analysis.

Declaration of competing interest

There are no conflicts of interest to report.