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: Acute graft-versus-host disease (aGVHD) remains a significant cause of morbidity and mortality following allogeneic stem cell transplantation (allo-SCT). CD74, also known as the HLA class II invariant chain, is expressed on the surface of antigen presenting cells (APCs) and involved in pro-survival signaling. Milatuzumab is a humanized IgG1_K monoclonal antibody that interacts with CD74 leading to rapid internalization and cytotoxicity independent of antibody crosslinking. Milatuzumab, therefore, 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 SCT prevented the development of GVHD, suppressed circulating cytokines, and reduced the mortality of the SCID mice (Chen, BBMT, 2013).

METHODS: We are performing an open-label, single-center phase 1 dose escalation trial to determine the maximum tolerated dose of milatuzumab when added to standard GVHD prophylaxis in the setting of reduced-intensity conditioning (RIC) for HLA matched (≥8/8) sibling or unrelated donor SCT. Patients are premedicated with dexamethasone and receive milatuzumab intravenously on Days -7, -4, -1, and +7. The initial starting dose was 8 mg/kg with continued dose escalation to 16 mg/kg 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, or ≥ grade 4 infusion reactions attributable to milatuzumab (CTCAE v4.0). Expected hematologic toxicities from SCT were excluded from this definition. Acute and chronic GVHD was recorded according to Consensus and NIH criteria, respectively.

RESULTS: Seven patients have been treated on trial with median follow up of 53 days post SCT (average 105 days; range 13-234). The median age is 59 years (range 26-70). Patients had a variety of hematologic malignancies (3 AML, 1 MDS, 1 ALL, 1 HD, & 1 MCL). Median Sorror comorbidity score (CMI) was 1 (range 0-8). Patients were in complete remission prior to SCT except for one MCL patient with partial response to prior therapy. Recipients received RIC with fludarabine (30 mg/m² days -7 to -3) and busulfan (0.8 mg/kg Q6 hours days -4 & -3 x8 doses) along with standard GVHD prophylaxis including tacrolimus and methotrexate (D+ 1, 3, 6, & 11). Donors were 8/8 HLA-matched siblings (UPNs 2, 4, & 7) or matched unrelated (UPNs 1, 3, 5, & 6). All patients received four doses of milatuzumab. Three individuals were initially treated with 8 mg/kg (DL1) and 3 received 16 mg/kg (DL2). At DL2, two of 3 patients had grade 5 sepsis with one having grade 4 respiratory failure. As a result, three more patients will be enrolled to DL1 to further assess safety; one has been treated thus far. The most common toxicities attributable to milatuzumab were grade 1-2 including GI complaints, nasal congestion, fever, parathesia, and urticaria. One patient had grade 1-2 infusion reactions on two occasions. Four of 7 patients had cutaneous aGVHD with 2 of 4 experiencing grade 1, one with grade 2, and one with grade 4 (table 1). One patient experienced grade 1 GI aGVHD. The grade 4 aGVHD (UPN 6) was histologically and phenotypically indistinguishable from toxic epidermal necrolysis/Stevens-Johnson syndrome and that patient was treated with brentuximab for steroid-refractory cutaneous GVHD. He subsequently died due to polymicrobial sepsis. Two other patients died, one from relapsed AML (UPN 4) and one from staphylococcal aureus sepsis (UPN 5).

CONCLUSIONS: While the grade 5 events in DL2 (16 mg/kg) were not considered specifically attributable to milatuzumab, DL1 has been expanded to further evaluate safety of this dose. Four patients have been enrolled at DL1 with only grade 1 and 2 aGVHD reported, either cutaneous or upper GI. We will continue to accrue 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.