Introduction: Large granular lymphocytic leukemia (LGLL) is a chronic, incurable lymphoproliferative disorder of cytotoxic T (CD8) and natural killer (NK) cells that leads to neutropenia, recurrent infections, and anemia requiring transfusions. No approved therapies exist, and chronic immunosuppression therapy makes long-term management challenging. DR-01 is a non-fucosylated human IgG antibody targeting CD94, expressed on terminal effector CD8+T cells, γδT cells, and NK cells leading to depletion of these cell populations by antibody-dependent cellular cytotoxicity including fratricide. Here we report preliminary results in LGLL patients as part of a Phase 1/2 open-label, dose-escalation study (NCT05475925) assessing DR-01 safety, pharmacokinetics (PK), pharmacodynamics and initial efficacy in patients with cytotoxic NK/T-cell malignancies.

Methods: LGLL patients who failed ≥1 prior line of therapy and cytotoxic lymphoma patients (see companion abstract) were enrolled. LGLL patients received DR-01 (0.3–10 mg/kg) intravenously (IV) in primary (C1D1/D15) or secondary (C1D1/D8/D15) induction regimens followed by monthly maintenance IV infusions. The first dose was given as a split dose on C1D1 and C1D2. Efficacy was assessed using ECOG E5998 response criteria (Loughran 2015).

Results: As of May 2025, 31 LGLL patients (pts) were enrolled: 21 (68%) were male; and median age was 64 years (range, 24–86). 23 (74%) were white, 4 (13%) were Asian, and 4 (13%) were black/other or not reported). ECOG performance status was: 0 (32%), 1 (61%), or 2 (7%) at study entry. Twenty-eight (90%) pts had T cell LGLL and 3 (10%) pts had NK cell LGLL. Primary indications for treatment were neutropenia (absolute neutrophil count (ANC) <500/uL) in 12 (39%), transfusion-dependent anemia in 11 (35%), symptomatic anemia in 6 (19%), and neutropenia (ANC <1500/uL) with recurrent infections in 2 (6%) patients. Median number of prior lines of therapy was 2 (range, 1–13). Prior therapies included methotrexate in 29 (94%), cyclophosphamide in 15 (48%), cyclosporine in 13 (42%), and alemtuzumab in 4 (13%), with 17 (55%) pts also receiving some other treatment including investigational agents. Time on DR-01 treatment at data cut-off ranged from 1 to 18 months, with 20 patients (65%) remaining on study treatment.The most frequent treatment-related adverse events (TRAEs) (>15%) were infusion-related reaction (IRR; 23%), fatigue (16%), nausea (16%); the majority were grade 1-2. No IRR led to dose reduction or discontinuation other than in the first patient enrolled before optimization of IRR prophylaxis was instituted. No deaths, dose-limiting toxicities, or serious TRAEs occurred.

Of 23 response-evaluable patients receiving primary or secondary induction regimen, the observed overall response rate (ORR) was 44%, including 6 patients (26%) with a hematologic complete response (CR) and 4 patients (17%) with a partial response (PR). Eight patients on study had not reached the first response assessment and were not evaluable for response at the time of data cut-off. Time to first response ranged from 0.9 to 1.8 months, with 8 of 10 responders reaching at least PR by the C2D1 response assessment. Among patients who achieved a CR, the primary indication for treatment was neutropenia in 4 patients and transfusion-dependent anemia in 2 patients. All patients achieving a response (PR or CR) remain in response on study treatment except for 1 patient who went on to allogeneic stem cell transplant. The longest duration of ongoing response (15+ months) was observed in a heavily pretreated patient who achieved a best response of CR and RBC transfusion independence after 7 lines of prior therapy. The secondary induction regimen (DR-01 on C1D1/D8/D15) has been selected for further evaluation. Of the 15 patients who received secondary induction regimen, the ORR was 60%, with 33% CRs and 27% PRs. DR-01 PK was linear within the dose range tested. Responses were accompanied by peripheral LGLL cell depletion, dominant LGLL clone eradication in the peripheral blood, and reduction of the cytotoxic marker, serum granzyme B.

Conclusions: Preliminary safety and efficacy data show that DR-01 is well-tolerated with a promising response rate and durable responses, supporting continued development of DR-01 as a therapy for LGLL.

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2025
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