Intense Immunosuppressive Therapy (anti-thymocyte globulin, alemtuzumab) As Salvage Therapy in Refractory T-Cell Large Granular Lymphocytic Leukemia and Pure Red Cell Aplasia

Background T-cell directed immunosuppression (IS: methotrexate, cyclosporine, and cyclophosphamide) is the main treatment modality applied for the therapy of immune single-lineage cytopenias including idiopathic neutropenia and pure red cell aplasia (PRCA). These two conditions are likely T-cell mediated and are often associated with T-cell large granular lymphocytic leukemia (T-LGL). The latter is thought to result from an originally polyclonal process evolving to a clonal proliferation of cytotoxic T-lymphocytes. Generally, response to 1^st line therapies is about 30%, whereas rates as high as 80-90% can be achieved with 2^nd, and 3^rd lines. However, a significant fraction of patients remains refractory to multiple therapies and constitutes a management challenge. These patients remain transfusion dependent and/or have severely depressed neutrophil counts refractory to granulocyte-colony stimulating factor (G-CSF). In this scenario, intense IS with anti-thymocyte globulin (ATG) and alemtuzumab is often considered a salvage option, but no systematic experience exists and only a few controlled clinical trials have been conducted. Particularly, we previously reported an overall response rate (ORR) of 63% (n=23) with low dose alemtuzumab (10 mg sc q week x10) and 2/2 with ATG (40 mg/kg/d x 4 days) in patients with PRCA and/or LGL. Previous experience showed an ORR of 74% in a phase II study of 19 T-LGL patients treated with alemtuzumab, whereas a literature meta-analysis showed an ORR of 33% in 24 patients with PRCA treated with ATG. To better rationalize salvage therapy for refractory immune cytopenias, we explored the effectiveness of these agents at our tertiary referral center.

Design and Methods We retrospectively examined treatment outcomes in 296 patients with LGL (113 had neutropenia and 73 anemia), and 78 patients with PRCA (+/- LGL). The study cohort had severe refractory cytopenia despite multiple treatment regimens and received salvage therapy with ATG and/or alemtuzumab. Complete response (CR) was defined as hemoglobin >10 g/dL, and absolute neutrophil count >1.0x10⁹/L. Partial response (PR) was defined not meeting CR criteria. Response to therapy was evaluated while on therapy (alemtuzumab) and 4 months post-therapy (ATG). Overall response rate (ORR) was calculated as the percentage of patients with both CR and PR over the total number of patients who received the drug. The response rate was not available for 4 and 3 cases in the ATG and alemtuzumab cohorts respectively.

Results A total of 62 patients who received salvage therapy with ATG (N=23) and alemtuzumab (N=39) for refractory cytopenia associated with LGL (N=38) and without LGL (N=24) were identified. Overall, the median age at disease onset was 58 years (IQR 45-69) with a 1.2 male to female ratio. On average, patients received 4 treatment modalities prior to ATG/alemtuzumab to which they did not respond or became refractory. CR rate (CRR) for patients treated with ATG was 42% (8/19) and ORR 89% (17/19). The CRR and ORR was 22% (8/36) and 81% (29/36), respectively in patients treated with alemtuzumab. No significant difference was observed in terms of ORR in patients treated with alemtuzumab compared to ATG (P = 0.45). In T-LGL cases, the presence of a STAT3 mutation did not impact an ORR to either alemtuzumab (31 vs 45% in STAT3 wild type) or ATG-treated cases (54 vs 38%). There was no significant difference in the LGL and PRCA (+/- LGL) cohorts treated with alemtuzumab (P = 0.89) and ATG (P = 0.13). Overall, no treatment-related death was registered, and toxicities were manageable. Alemtuzumab was held if absolute lymphocyte count was <200/µL. Of note, only one patient had CMV re-activation in our cohort.

Conclusion Our data shows that alemtuzumab and ATG represent salvage IS regimens highly effective for the treatment of T-LGL and PRCA refractory to multiple lines of therapy with ORR higher if compared to historical data. This therapy resulted in a durable response in both T-LGL and PRCA (+/- LGL) with a good safety profile. The use of low dose alemtuzumab greatly decreases the complication rate and tolerability.

Thota:BMS: Membership on an entity's Board of Directors or advisory committees; Blueprint Medicine: Membership on an entity's Board of Directors or advisory committees. Carraway:CTI Biopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Stemline: Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Other: DSMB; Syndax: Other: DSMB; Takeda: Other: DSMB; BMS: Consultancy, Honoraria, Speakers Bureau. Maciejewski:Apellis Pharmaceuticals: Consultancy; Alexion: Consultancy.