A Phase I Study of Milatuzumab for Prevention of Acute Graft Versus Host Disease Following Reduced-Intensity Conditioning Allogeneic Stem Cell Transplant in Patients with Hematologic Malignancies

INTRODUCTION: Milatuzumab is a humanized IgG1_Kmonoclonal antibody that interacts with CD74, leading to rapid internalization and cytotoxicity independent of antibody crosslinking. CD74, also known as HLA class II invariant chain, is a cell-surface antigen expressed on antigen presenting cells (APCs) and involved in pro-survival signaling. Thus, milatuzumab has potential to inhibit APC-mediated T-cell proliferation and decrease the risk of aGVHD. In a xenogeneic SCID mouse model, milatuzumab administered prior to transplant prevented the development of GVHD, suppressed circulating cytokines, and reduced the mortality of the SCID mice (Chen et al, BBMT, 2013).      

METHODS: We are performing an open-label, single-center phase 1 dose escalation trial to determine the maximum tolerated dose (MTD) of milatuzumab when added to standard GVHD prophylaxis using reduced-intensity conditioning (RIC) for HLA matched (≥8/8) sibling or unrelated SCT. Patients (pts) are premedicated with dexamethasone and receive milatuzumab intravenously on days -7, -4, -1, and +7. The initial starting dose was 8 mg/kg (DL1) with dose escalation to 16 mg/kg (DL2) and 20 mg/kg in cohorts of 3-6 until unacceptable toxicity. Dose limiting toxicities are defined as graft failure, any ≥ grade 4 organ toxicities excluding expected hematologic toxicities from SCT, or ≥ grade 4 infusion reactions attributable to milatuzumab. Acute and chronic GVHD was recorded according to Consensus and NIH criteria, respectively.

RESULTS: Nine pts have been treated with median follow up of 56 days post transplant (average 121 days; range 13-294). The median age is 57 years (range 26-70). Pts had a variety of hematologic malignancies. Median Sorror comorbidity score was 1 (range 0-8). Recipients received RIC with fludarabine (30 mg/m²days -7 through -3) and busulfan (0.8 mg/kg every 6 hours days -4 and -3 for total of 8 doses) along with tacrolimus and methotrexate (D+ 1, 3, 6, & 11). Donors were 8/8 HLA-matched siblings or matched unrelated. All pts received four doses of milatuzumab and 3 or 4 doses of methotrexate. Three individuals were initially treated at DL1 followed by 3 pts at DL2. At DL2, one pt died from relapsed AML, and 2 pts died from grade 5 sepsis. At DL2, only one experienced GVHD (grade 4 cutaneous that was indistinguishable from Stevens-Johnson Syndrome). As a result, three more pts were enrolled to DL1 to assess safety. Only 1 of 6 pts at DL1 had toxicity attributable to milatuzumab (grade 1 tremor). In DL1, 3 of 6 had aGVHD with 2 of 3 experiencing grade 1 and one grade 2 cutaneous GVH.

CONCLUSIONS: While the grade 5 events in DL2 (16 mg/kg) were not considered specifically attributable to milatuzumab, DL1 (8mg/kg) has been well tolerated without any grade 3 GVHD. We will continue to monitor at DL1 and pending tolerability may amend the protocol to test an intermediate dose of 12 mg/kg. Milatuzumab remains an intriguing potential agent to prevent aGVHD.